Bez nadpisu

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Basic physiologic properties of
myocardium automaticity conduction excitabilit
y (refractoriness) contractility
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M (?1)
Aorta
SA uzel
VCI
Sval síní
AV uzel
?1
Subend. prední ram.
SA uzel
Spol. svazek
Internodální spoje
Raménko
AV uzel
Purk. vlákna
Sval komor
Hisuv svazek
Pravé raménko
ECG
T
P
U
QRS
Purkynova vlákna
0.6
0.4
0.2
Subendokardiální zadní raménko
Cas (s)
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Effective refractory period The period that
must pass after the upstroke of a conducted
impulse in a part of the heart before a new
action potential can be propagated in that cell
or tissue.
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Arrhythmias are defined by exclusion- i.e., any
rhythm that is not a normal sinus rhythm (NSR) is
an arrhythmia.
Abnormal automaticity ? Sick sinus syndrome ?
Pacemaker activity that originates anywhere other
than in the sinoatrial node abnormal
autom. Abnormal conduction ? Conduction of an
impulse that does not follow the physiological
path (defined previously) ? reenters tissue
previously excited reentry
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Supraventricular tachycardia A reentrant a
arrhythmia that travels through the AV node it
may also be conducted through atrial and
ventricular tissue as part of the reentrant
circuit Ventricular tachycardia A very common
arrhythmia, associated often with myocardial
infarction ventricular tachycardia (a) may
involve abnormal automaticity or abnormal
conduction, (b) usually impairs cardiac output,
and (c) may deteriorate into ventricular
fibrillation requires prompt management
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Atrial, ventricular fibrillation Arrhythmias
involving rapid reentry and chaotic movement of
impulses through the tissue of the atria or
ventricles ventricular, but not atrial,
fibrillation is fatal within a few minutes if not
terminated
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A few of the clinically important arrhythmias
are atrial flutter, atrial fibrillation
(AF), atrioventricular nodal reentry (a common
type of SVT), premature ventricular beats
(PVBs), ventricular tachycardia (VT),
ventricular fibrilation (VF).
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Drug class Classifications The antiarrhythmic
agents are often classified using a system
loosely based on the channel or receptor
involved. This system specifies four classes,
usually denoted by Roman numerals I through
IV I. Sodium channel blockers II. Beta
adrenoceptor blockers III. Potassium channel
blockers IV. Calcium channel blockers A
miscellaneous class includes adenosine,
digitalis, potassium iod, and magnesium ion.
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Class I - sodium channel blocking drugs
all of them behave like local anesthetics.
These agents are frequently subdivided
according to their effects on action potential
duration and upstroke velocity (Vmax)
Prototypes Class IA agents (prototype,
quinidine) prolong the action potential and
reduce Vmax (). Class IB drugs shorten the
action potential in some cardiac tissues
(prototype, lidocaine) and ? Vmax (). Class IC
drugs have no effect on action potential duration
(prototype, flecainide) but ??? Vmax.
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Mechanism of action all class I drugs slow or
abolish abnormal pacemakers and slow or block
conduction (especially in depolarized cells)
wherever these processes depend on sodium
channels Useful sodium (and calcium)
channel-blocking drugs bind to their receptors
much more readily when the channel is open or
inactivated than when it is fully repolarized and
recovered from its previous activity. Ion
channels in arrhythmic tissue spend more time in
the open or inactivated states than do channels
in normal tissue. Therefore, these antiarrhytmic
drugs block channels in abnormal tissue more
effectively than channels in normal tissue.
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As a result, antiarrhythmic sodium (and calcium)
channel blockers are statedependent in their
action, ie, selectively depressants on tissue
that is frequently depolarizing (eg, during a
fast tachycardia) or is relatively depolarized
during rest (by hypoxia). Drugs with classIA
action Quinidine is the class IA prototype.
procainamide, disopyramide and amiodarone
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Quinidine C a r d i a c effects direct
(concentration dependent) A-V
depressant negative inotropic concentration
independent parasympatolytic increase action
potential (AP) duration and the effective QT
interval. E x t r a c a r d i a c effects
quinidine possesses alpha adrenoceptor-blocking
properties that can cause vasodilation and a
reflex increase in sinoatrial nodal rate.
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Pharmacokinetics Quinidine is usually
administered orally and is rapidly absorbed from
the gastrointestinal tract. It is 80 bound to
plasma proteins. Its half-life is about 6 hours
and may be longer in patients with congestive
cardiac failure or hepatic or renal disease. Is
is usually administered as the sulfate,
gluconate, or polygalacturonate salt. The usual
dose of 0.2-0.6 g of quinidine sulfate is given
2-4times daily. Parenteral administration of
quinidine is occasionally necessary. Quinidine is
absorbed after i.m. injection of the sulfate in
oil or the aqueous gluconate preparation. IV
administration is usually associated with a
decline in blood pressure as a result of its
peripheral vasodilating action.
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Toxicity Quinidine has antimuscarinic actions
in the heart that inhibit vagal effects. This can
overcome some of its direct membrane effect and
lead to increased sinus rate and increased
atrioventricular conduction. This action can be
prevented by prior administration of a drug
that slows atrioventricular conduction
(verapamil, a beta-blocker, digitalis). A small
percentage (1-5) of patients given quinidine
develop a syndrom called "quinidine syncope"
characterized by recurrent light-headedness and
episodes of fainting.? torsade de pointes
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These toxic effects are more likely to occur
when the serum concentrations exceed 5 ug/ml and
in the presence of high serum potassium levels (gt
5mmol/l) Widening of the QRS duration by 30 by
quinidine administration is usually considered
premonitory of serious toxicity. Toxic
concentrations may depress contractility and
lower blood pressure. Quinidine causes
cinchonism (headache, tinnitus) cardiac
depression gastrointestinal upset and allergic
reactions (eg, thrombocytopenic
purpura). Quinidine reduces the clearance of
digoxin and may increase the serum concentration
of the glycoside to dangerous levels.
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Therapeutic use Quinidine is used in nearly
every form of arrhythmia premature atrial
contractions, paroxysmal atrial fibrillation and
flutter, intra-atrial and atrioventricular nodal
reentrant arrhythmias, premature ventricular
contractions, and ventricular tachycardias.
especially chronic outpatient treatment.
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Procainamide The electrophysiological effects
of procainamide are similar to those of
quinidine. Procainamine s cardiotoxic effects
are similar to those of quinidine. The most
troublesome adverse effect is a syndrome
resembling lupus erythematosus and usually
consisting of arthralgia and arthritis.
Approximately one-third of patients receiving
long-term procainamide therapy develop this
syndrome.
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Pharmacokinetics Procainamide can be
administered safely IV, i.m. and is well absorbed
orally. The major metabolite is
N-acetylprocainamide (NAPA) - pharmacologically
active. Excessive accumulation of NAPA has been
implicated in torsade de pointes during
procainamide therapy. Some individuals rapidly
acetylate procainamide and develop high level of
N-acetylprocainamide. The lupus syndrom appears
to be less common in these patients.
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One arrhythmia, called torsade de pointes, is
particularly associated with quinidine and other
drugs that prolong AP duration (except
amiodarone). Hyperkalemia usually exacerbates
the cardiac toxicity of class I drugs. Treatment
of overdose with these agents is usually carried
out with sodium lactate (to reverse drug-induced
arrhythmias) and pressor sympathomimetics (to
reverse drug-induced hypotension).
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Drugs with class IB actions Lidocaine is the
prototype IB drug. This drug affects ischemic or
depolarized Purkinje and ventricular tissue and
has little effect on atrial tissue the drug
reduces action potential duration, but because
it slows recovery of sodium channels from
inactivation, it does not shorten (or may even
prolong) the effective refractory period.
Mexiletine, tocainide and fenytoin have similar
effects. Because these agents have little effects
on normal cardiac cells, they have little effects
on the ECG..
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Lidocaine is useful in acute ventricular
arrhythmias, especially those involving ischemia,
eg, following myocardial infarction. Atrial
arrhythmias are not respondsive unless caused by
digitalis. Lidocaine is usually given
intravenously, but IM administration is also
possible. Mexiletine and tocainide have
similar actions but can be given orally.
Typical local anesthetic toxicity CNS
stimulation, including convulsions
cardiovascular depression (usually minor)
allergy (usually rashes but may extend to
anaphylaxis). Tocainide may cause
agranulocytosis. These drugs may also
precipitate arrhythmias, but this is less common
than with class IA drugs. Hyperkalemia, however,
increases cardiac toxicity.
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Drugs with class IC action Flecainide is the
prototype drug with class IC actions. Encainide
(recently withdrawn), moricizine, and propafenone
These drugs have no effect on ventricular
action potential duration or the QT interval.
They are powerful depressants of sodium
current, however, and can markedly slow
conduction velocity in atrial and ventricular
cells
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Flecainide is effective in both atrial and
ventricular arrhythmias, but is approved only for
(a) refractory ventricular tachycardias that tend
to progress to VF at unpredictable times,
resulting in "sudden death", and (b) certain
intractable supraventricular arrhythmias. more
likely than other antiarrhythmic drugs to
exacerbate or precipitate arrhythmias
(proarrhythmic effect). For this reason, the
class IC drugs are limited to last report
applications in refractory tachycardias. These
drugs also cause local anesthetic-like CNS
toxicity. Hyperkalemia increases the cardiac
toxicity of these agents.
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CLASS II (BETA-BLOCKERS) Propranolol and esmolol
are the prototype antiarrhythmic beta-blockers.
Their mechanism in arrhythmias is primarily
cardiac beta blockade and reduction in cAMP,
which results in the reduction of both sodium and
calcium currents and the suppression of abnormal
pacemakers. The AV node is particularly
sensitive to beta-blockers the PR interval is
frequently prolonged by class II drugs (Table
14-2). Under some conditions, they may have
some direct local anesthetic (membrane
stabilizing) effect in the heart, but this is
probably rare at the concentrations achieved
clinically.
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Esmolol a very short-acting beta-blocker for
intravenous administration, is used almost
exclusively in acute surgical arrhythmias.
Propranolol, metoprolol, and timolol are
commonly used as prophylactic drugs in patients
who have has a myocardial infarction. These drugs
provide a protective effect for two years or more
after the infarct. The toxicities of
beta-blockers are the same when used as
antiarrhythmics or in any other application.
However, patients with arrhythmias are often
more prone to b-blocker-induced depression of
cardiac output than are patients with normal
hearts.
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CLASS III (POTASSIUM CHANNEL BLOCKERS) Sotalol i
s a chiral compound, ie, it has two optical
isomers. One isomer is an effective beta-blocker,
the other provides most of the antiarrhythmic
action. The clinical preparation contains both
isomers. Bretylium is an older drug that
combines sympathoplegic actions and a potassium
channel-blocking effect.
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Amiodarone most efficacious antiarrhythmic
drug. broad spectrum it blocks sodium, calcium,
and potassium channels and beta adrenoceptors.
Toxicity thyroid dysfunction (hyper- or
hypothyroidism), paresthesias, tremor,
microcrystalline deposits in the cornea and skin,
and pulmonary fibrosis. Amiodarone rarely causes
new arrhythmias.
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Mechanism effects prolongation of the action
potential duration is cause by blockade of
potassium channels that are responsible for the
repolarization of the action potential. AP
prolongation results in an increase in effective
refractory period and reduces the ability of the
heart to respond to rapid tachycardias. Sotalol
and amiodarone (and quinidine) produce this
effect on most cardiac cells the action of these
drugs is therefore apparent in the ECG.
N-acetylprocainamide (NAPA), a metabolite of
procainamide, also significatnly prolongs the
action potential and the QT interval.
Bretylium, on the other hand, produces AP
prolongation mainly in ischemic cells, and causes
little change in the ECG.
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C. Clinical uses toxicities Bretylium is
used only in the treatment of refractory
postmaocardial infarction arrhythmias, eg,
recurrent ventricular fibrillation. The drug is
rarely used. It may precipitate new arrhythmias
or marked hypotension. Sotalol is more
generally useful and is available by the oral
route (Table 14-2). Sotalol may precipitate
torsade de pointes arrhythmia, as well as signs
of excessive beta blockade such as sinus
bradycardia or asthma. The toxicities of
amiodarone and other class IA drugs (which share
the potassium channel-blocking action of class
III agents) are discussed with the class IA drugs.
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CLASS IV (CALCIUM CHANNEL BLOCKERS) A.
Prototype Verapamil is the prototype. Diltiazem
is also an effective antiarrhythmic drug although
it is not approved for this purpose. Nifedipine
and the other dihydropyridines are not useful as
antiarrhythmics, probably because they decrease
arterial pressure sufficiently to evoke a
compensatory sympathetic discharge to the heart.
The latter effect would facilitate rather than
suppress arrhythmias.
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B. Mechanism effects Verapamil and diltiazem
are effective in arrhythmias that must traverse
calcium-dependent cardiact tissue (eg, the
atrioventricular node). These agents cause a
state-dependent selective depression of calcium
current in tissues that require the participation
of L-type calcium channels (Figure 14-7).
Conduction velocity is decreased and effective
refractory period is increased by these drugs. PR
interval is consistently increased (Table 14-2).
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C. Clinical use toxicities Calcium channel
blockers were drugs of choice in atrioventricular
nodal reentry (also known as nodal tachycardia
and supraventricular tachycardia) until adenosine
became available they are highly effective in
this type of arrhythmia. Their major use now is
in the prevention of these nodal arrhythmias.
These drugs are orally active verapamil is also
availabel for parenteral use (Table 14-2). The
most important toxicity of verapamil as an
antiarrhythmic relates to excessive pharmacologic
effect, since cardiac contractility can be
significantly depressed. See chapter 12 for
additional discussion of toxicity. Amiodarone has
moderate calcium channel- blocking activity.
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MISCELLANEOUS ANTIARRHYTHMIC DRUGS A.
Adenosine Adenosine is a normal component of the
body, but when given in high dosage (6-12 mg) as
an intravenous bolus, the drug markedly slows
conduction in the atrioventricular node (Table
14-2). Adenosine is extremely effective in
abolishing AV nodal arrhythmias and, because of
its very low toxicity, has become the drug of
choice for this arrhythmia. Adenosine has an
extremely short duration of action these effects
do not limit the use of the drug.
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B. Digitalis The actions of digitalis were
discussed in Chapter 13. The cardiac
parasymathomimetic action of digoxin is sometimes
exploited in the treatment of rapid atrial or AV
nodal arrhythmias. In atrial flutter or
fibrillation, digitalis slows AV conduction
sufficiently to protect the ventricles from
excessively high rates. In AV nodal reentrant
arrhythmias, digitalis may exert enough
depressant effect to abolish the arrhythmia. The
latter appliaction of digitalis has become less
common since the development of calcium channel
blockers and adenosine as antiarrhythmic drugs.
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C. Potassium ion Potassium depresse ectopic
pacemakers, including those caused by digitalis
toxicity. Hypokalemia is associated with
increased incidence of arrhythmias, especially in
patients receiving digitalis. Conversely,
excessive potassium levels depress conduction and
can measured and, if abnormal, normalized. D.
Magnesium ion Magnesium has not been as well
studied as potassium but appears to have similar
depressant effects on digitalis-induced
arrhythmias. Magnesium also appears to be
effective in some cases of torsade de pointes
arrhythmia.
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