[referat] Antiarrhythmic drugs in elderly

Antiarrhythmic drugs in elderly
Presented by: Muhammad Afzalurrahman Putranda
Consultant: dr. Achmadi Eko Sugiri, Sp.PD
Presented on 24 December 2019 at General Hospital of Moehamad Djoen Sintang

Background
 Human aging is a global issue.
 Based on census and population projections from 1950 to 2050, there has
been a worldwide transformation of the distribution of the population by
age, from a population pyramid to a population dome.
 With the advance in overall age comes an increase in the incidence of
cardiovascular diseases, including cardiac arrhythmias
 Arrhythmias (also termed dysrhythmias) and are among the most common
clinical problems encountered. The presentations o arrhythmias range rom
common benign palpitations to severe symptoms of low cardiac output
and death.
Lee HC et al. Using antiarrhythmic drugs in elderly patients. J Geriatr Cardiol 2011; 8: 184−194.
Lilly LS. Pathophysiology of heart disease. 6th ed. Philadelphia: Wolters Kluwer; 2016.

Heart electrical activity
 The source of this electrical activity is a network of specialized cardiac
muscle fibers called autorhythmic fibers
 Autorhythmic fibers repeatedly generate action potentials that trigger
heart contractions.
 During embryonic development, only about 1% of the cardiac muscle
fibers become autorhythmic fibers
 act as a pacemaker
 form the conduction system, a network of specialized cardiac muscle fibers that
provide a path for each cycle of cardiac excitation to progress through the
heart.
Tortora GJ, Derrickson B. Principles of Anantomy and Physiology. 12th ed. Hoboken: John Wiley & Sons; 2009.

 P wave represents atrial depolarization, which spreads from the SA node
through contractile fibers in both atria.
 The QRS complex represents rapid ventricular depolarization, as the action
potential spreads through ventricular contractile fibers.
 The T wave indicates ventricular repolarization and occurs just as the
ventricles are starting to relax. The T wave is smaller and wider than the
QRS complex because repolarization occurs more slowly than
depolarization.
 During the plateau period of steady depolarization, the ECG tracing is flat.

Arrhythmia
 also termed dysrhythmias  abnormalities of the electric rhythm
 The presentations of arrhythmias range from common benign palpitations
to severe symptoms of low cardiac output and death
 Normal rhythm range from 60-100 bpm
 Bradycardia
 Tachycardia

Pathophysiology

Classification

Physiology basics of antiarrhythmic
therapy
 Appropriate treatment of a rhythm disorder depends on its severity and its
likely mechanism.
 Additional therapy to prevent recurrences is guided by the etiology of the
rhythm disturbance.
 Correctable actors that contribute to abnormal impulse formation and
conduction (such as ischemia or electrolyte abnormalities) should be
corrected.

Strategies to interrupt reentry

Antiarrhythmic agents
 Clinically, divided as
 Supraventricular
 Supraventricular and ventricular
 Ventricular
 Based on effect on electric activity myocardial cells
(Vaughan–Williams classification)
 Class I: Na+ channel blockade
 Class II: β-Adrenergic receptor blockade
 Class III: K+ channel blockade
 Class IV: Ca2+ channel antagonists
pionas.pom.go.id/ioni/bab-2-system-kardiovaskuler-0/22-aritmia/221-antiritmia/ accessed on Dec 20, 2019

Special condition (elderly)
Cardiac electrophysiological properties change with age
 intrinsic heart rate decreases with age.
 the PR interval becomes prolonged with age
 conduction system changes in the form of RBBB are more common
 atrial and ventricular ectopies are known to increase with age
 age-related non-specific ST-T wave changes are common
 the QT interval increases with age
Buku Ajar Boedhi-Darmojo Geriatri (Ilmu Kesehatan Lanjut Usia) Edisi ke-5, BP FKUI, 2014.

Epidemiology in elderly
Incidence of arrhythmias in healthy people >75 years
Atrial Fibrillation 11%
Ventricular ectopic beats 56%
Frequent ventricular ectopic beats 12%
Multifocal ventricular beats 22%
Salvoes of ventricular ectopic beats
Ventricular tachycardia
9%
Complete heart block 1%
A. Martin: CV problems in the elderly, CV-Update, 1984 in Buku Ajar Boedhi-Darmojo Geriatri (Ilmu Kesehatan Lanjut Usia) Edisi ke-5, BP FKUI, 2014. page 393

Class I (Na+ channel blocker)
 Ia: Slows Phase 0 depolarization in ventricular muscle fibers
 Ib: Shortens Phase 3 repolarization in ventricular muscle fibers
 Ic: Markedly slows Phase 0 depolarization in ventricular muscle fibers
Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. Sixth Edition. Philadelphia: Wolters Kluwer. 2015.

Class IA antiarrhythmic drugs: Quinidine,
procainamide, and disopyramide
 Mechanism of action:
 binds to open and inactivated sodium channels and prevents sodium influx, thus
slowing the rapid upstroke during phase 0.
 decreases the slope of phase 4 spontaneous depolarization, inhibits potassium
channels, and blocks calcium channels.
 Therapeutic uses:
 Quinidine is used in the treatment of a wide variety of arrhythmias, including atrial,
AV junctional, and ventricular tachyarrhythmias.
 Procainamide is available in an IV formulation only and may be used to treat acute
atrial and ventricular arrhythmias.
 Disopyramide is used in the treatment of ventricular arrhythmias as an alternative to
procainamide or quinidine for maintenance of sinus rhythm in atrial fibrillation or
flutter

Class IA antiarrhythmic drugs: Quinidine,
procainamide, and disopyramide
 Pharmacokinetics
 rapidly and almost completely absorbed after oral administration
 Primally metabolism in liver
 eliminated via the kidney, and dosages may need to be adjusted in patients
with renal failure.
 Adverse effects:
 may induce the symptoms of cinchonism (for example, blurred vision, tinnitus,
headache, disorientation, and psychosis)
 may cause hypotension
 anticholinergic adverse effects of the class IA drugs (for example, dry mouth,
urinary retention, blurred vision, and constipation)

Class IB antiarrhythmic drugs:
Lidocaine and mexiletine
 Useful in treating ventricular arrhythmias
 MOA: In addition to sodium channel blockade, lidocaine and mexiletine
shorten phase 3 repolarization and decrease the duration of the action
potential
 Therapeutic uses:
 lidocaine may be useful as an alternative of amiodarone in VT
 Lidocaine may also be used in polymorphic VT or in combination with
amiodarone for VT storm
 Mexiletine is used for chronic treatment of ventricular arrhythmias, often in
combination with amiodarone.

Class IB antiarrhythmic drugs:
Lidocaine and mexiletine
 Pharmacokinetics:
 Lidocaine is given intravenously because of extensive first-pass transformation by
the liver, which precludes oral administration.
 As lidocaine is a high extraction drug, drugs that lower hepatic blood flow (β-
blockers) may require dose adjustment
 Mexiletine is well absorbed after oral administration. It is metabolized in the liver
primarily by CYP2D6 to inactive metabolites and excreted mainly via the biliary
route.
 Central nervous system (CNS) effects include nystagmus (early indicator of toxicity),
drowsiness, slurred speech, paresthesia, agitation, confusion, and convulsions
 Nausea, vomiting, and dyspepsia are the most common adverse effects of
mexiletine

Class IC antiarrhythmic drugs:
Flecainide and propafenone
 Mechanism of action
 Flecainide [FLEK-a-nide] suppresses phase 0 upstroke in Purkinje and
myocardial fibers.
 also blocks potassium channels leading to increased action potential duration
 Therapeutic uses
 Flecainide is useful in the maintenance of sinus rhythm in atrial flutter or
fibrillation in patients without structural heart disease and in treating refractory
ventricular arrhythmias
 Use of propafenone is restricted mostly to atrial arrhythmias: rhythm control of
atrial fibrillation or flutter and paroxysmal supraventricular tachycardia
prophylaxis in patients with AV reentrant tachycardias

Class IC antiarrhythmic drugs:
Flecainide and propafenone
 absorbed orally and is metabolized
 by CYP2D6 to multiple metabolites. The parent drug and metabolites
 are mostly eliminated renally, and dosage adjustment may be required in renal
disease
 generally well tolerated, with blurred vision, dizziness, and nausea more
often
 may also cause bronchospasm

Class II antiarrhythmic drugs
 Class II agents are β-adrenergic antagonists, or β-blockers.
 diminish phase 4 depolarization and, thus, depress automaticity, prolong
AV conduction, and decrease heart rate and contractility
 Metoprolol is the β-blocker most widely used in the treatment of cardiac
arrhythmias. Compared to nonselective β-blockers, such as propranolol, it
reduces the risk of bronchospasm
 extensively metabolized in the liver
 It has a fast onset of action and a short half-life, making it ideal for acute
situations and also limiting its adverse effect profile

Class III antiarrhythmic drugs
 Class III agents block potassium channels and, thus, diminish the outward
potassium current during repolarization of cardiac cells.
 All class III drugs have the potential to induce arrhythmias.
 Amiodarone
 Dronedarone
 Sotalol
 Dofitilede
 Ibutilide

Amiodarone
 MoA
 Its dominant effect is prolongation of the action potential duration and the
refractory period by blocking K+ channels
 Therapeutic uses
 effective in the treatment of severe refractory SVT and VT. mainstay of therapy
for the rhythm management of AF or A flutter

 incompletely absorbed after oral administration.
 The drug is unusual in having a prolonged half-life of several weeks,
 distributes extensively in adipose tissue.
 Full clinical effects may not be achieved until months after initiation of
treatment, unless loading doses are employed
 Adverse effect
 pulmonary fibrosis, neuropathy, hepatotoxicity, corneal deposits, optic neuritis,
blue-gray skin discoloration, and hypo- or hyperthyroidism

 Dronedarone is a benzofuran amiodarone derivative, which is less
lipophilic, has lower tissue accumulation, and has a shorter serum half-life
than amiodarone
 it has class I, II, III, and IV actions
 better adverse effect profile than amiodarone but may still cause liver
failure.
 CI: symptomatic heart failure or permanent AF
 used to maintain sinus rhythm in AF or A flutter, but it is less effective than
amiodarone

 Sotalol, although a class III antiarrhythmic agent, also has potent
nonselective β-blocker activity
 Sotalol blocks a rapid outward potassium current
 used for maintenance of normal sinus rhythm in patients with AF, A flutter,
or refractory paroxysmal SVT and in the treatment of VT
 β-blocking properties  commonly used for LVH or atherosclerotic heart
disease
 the typical adverse effects associated with β-blockers
 risk of proarrhythmic effects initiated in the hospital to monitor QT
interval

 Dofetilide is a pure potassium channel blocker.
 It can be used as a first-line antiarrhythmic agent in patients with
persistent AF and HF or in those with CAD.
 risk of proarrhythmia  initiation is limited to the inpatient setting.
 The half-life of this oral drug is 10 hours.
 The drug is mainly excreted unchanged in the urine.
 Drugs that inhibit active tubular secretion are contraindicated.

 Ibutilide is a potassium channel blocker that also activates the inward
sodium current (mixed class III and IA action).
 Ibutilide is the drug of choice for chemical conversion of AF, but electrical
cardioversion has supplanted its use.
 Ibutilide undergoes extensive first-pass metabolism and is not used orally.
 Because of the risk of QT prolongation and proarrhythmia, ibutilide
initiation is limited to the inpatient setting.

Class IV antiarrhythmic drugs
 Class IV drugs are the nondihydropyridine CCB
 verapamil
 diltiazem
 the major effect of CCB is on vascular smooth muscle and the heart
 bind only to open depolarized voltage-sensitive channels
 a decreased rate of phase 4 spontaneous depolarization
 also slow conduction in tissues that are dependent on calcium currents,
such as the AV and SA nodes
 useful in treating reentrant SVT and in reducing the ventricular rate in A
flutter and AF

Other antiarrhythmic drugs
Digoxin
 inhibits the Na+/K+-ATPase pump
 ultimately shortening the refractory period in atrial and ventricular myocardial
cells while prolonging the effective refractory period and diminishing
conduction velocity in the AV node
 used to control ventricular response rate in AF and A flutter
 sympathetic stimulation easily overcomes the inhibitory effects of digoxin
 toxic concentrations  digoxin causes ectopic ventricular beats that may result
in VT and fibrillation
 Serum trough concentrations of 1.0 to 2.0 ng/mL are desirable for atrial
fibrillation or flutter, whereas lower concentrations of 0.5 to 0.8 ng/mL are
targeted for systolic heart failure

Adenosine
 a naturally occurring nucleoside, but at high doses, the drug decreases
conduction velocity, prolongs the refractory period, and decreases
automaticity in the AV node.
 Intravenous adenosine is the drug of choice for abolishing acute SVT.
 It has low toxicity but causes flushing, chest pain, and hypotension.
 Adenosine has an extremely short duration of action (approximately 10 to
15 seconds) due to rapid uptake by erythrocytes and endothelial cells.

Magnesium sulfate
 Magnesium is necessary for the transport of sodium, calcium, and
potassium across cell membranes
 slows the rate of SA node impulse formation and prolongs conduction
time along the myocardial tissue
 IV magnesium sulfate is the salt used to treat arrhythmias, as oral
magnesium is not effective in the setting of arrhythmia
 the drug of choice for treating the potentially fatal arrhythmia torsades de
pointes and digoxin-induced arrhythmias

Digoxin toxicity
 Digoxin toxicity can emerge during long-term therapy as well as after an
overdose.
 the serum digoxin concentration therapeutic range
 0.8–2.0 nanogram/mL
 0.5–0.9 nanogram/mL (for heart failure)
 Chronic toxicity is far more common than acute intoxication
 several conditions increase sensitivity to digoxin  may develop toxicity
even within the therapeutic range
 hypokalaemia, hypomagnesaemia, hypercalcaemia, myocardial ischaemia,
hypoxaemia and acid–base disturbances
Matthew Pincus. Management of digoxin toxicity. Aust Prescr 2016;39:18–20.

Typical ECG change in patient with digoxin prescribing
Curved ST segment depression
9. https://ecgwaves.com/topic/digoxin-ecg-changes-arrhythmias-digoxin-digitalis/ accessed on Dec 24, 2019.

Muñoz NL, Buendía AB, and Manterola FA. Electrocardiographic Changes After Suicidal Digoxin Intoxication in a Healthy Woman. The Open Cardiovascular Medicine Journal 2017; 11: 58-60.

Vyas A, Bachani N, Thakur H, Lokhandwala Y. Digitalis toxicity: ECG vignette. Indian Heart Journal 2016; 68: s223-5.
Above, an ECG of 30-year-old woman with dilated cardiomyopathy (LVEF 0.25) was admitted for recurrent vomiting for 3 days. She had been on digoxin
and frusemide. Below, a ladder diagram depicting the electrophysiological phenomenon for the rhythm.

Management
 Digoxin-specific antibody fragments
 Safe and effective, but high-cost
 Activated charcoal  2 hrs acute ingestion
 Correction potassium level (hypokalemia)
 Arrhythmias
 Lignocaine  ventricular tachyarrhythmias
 Atropine  bradyarrhythmias.
 Cardioversion should be avoided  can result in v. fibrillation
 Restarting digoxin
Pincus M . Management of digoxin toxicity. Aust Prescr 2016;39:18–20.

Conclusions
 Elderly patients are avid consumers of medications, which increases the
risk of drug-drug interactions.
 Age-related alterations in drug pharmacokinetics, in hepatic metabolism,
and in renal elimination can be pronounced for some drugs and are often
under-appreciated.
 Potential drug-drug and drug-disease interactions are common and must
be scrutinized for each patient.
 All these issues may have a significant impact on the health-related quality
of life in the elderly.

Conclusions
 Digoxin toxicity can emerge during long-term therapy as well as after an
overdose.
 It can occur even when the serum digoxin concentration is within the
therapeutic range.
 Toxicity causes anorexia, nausea, vomiting and neurological symptoms. It
can also trigger fatal arrhythmias
Pincus M . Management of digoxin toxicity. Aust Prescr 2016;39:18–20.

Conclusions
 Digoxin-specific antibody fragments are safe and effective in severe
toxicity.
 Monitoring should continue after treatment because of the small risk of
rebound toxicity.
 Restarting therapy should take into account the indication for digoxin and
any reasons why the concentration became toxic.
 A conservative medical management, with a watchful-waiting strategy
under intensive surveillance, is safe and effective
Muñoz NL, Buendía AB, and Manterola FA. Electrocardiographic Changes After Suicidal Digoxin Intoxication in a Healthy Woman. The Open Cardiovascular Medicine Journal 2017; 11: 58-60.
Vyas A, Bachani N, Thakur H, Lokhandwala Y. Digitalis toxicity: ECG vignette. Indian Heart Journal 2016; 68: s223-5.

[referat] Antiarrhythmic drugs in elderly

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