ANTI-ARRHYTHMIC DRUGS - Increasing the pacing threshold also can inhibit

triggered activity arising from:

Class Mechanism of Comment
o delayed afterdepolarization (DAD)
action o early afterdepolarization (EAD)
IA Na+ channel Slows Phase 0 - Many Na+ CB also decrease phase 4 (Action
blocker depolarization in ventricular membrane potential) slope
muscle bers
IB Na+ channel Shortens Phase 3
blocker repolarization in ventricular
muscle bers
IC Na+ channel Markedly slows Phase 0
blocker depolarization in ventricular
muscle bers
II B-Adrenoreceptor Inhibits Phase 4
blocker depolarization in SA and AV
nodes
- Other effects of Na+ channel blocking:
III K+ channel blocker Prolongs Phase 3 o may decrease conduction sufficiently to
repolarization in ventricular extinguish the propagating reentrant wavefront
muscle bers o also shifts the voltage dependence of recovery
IV Ca2+ channel Inhibits action potential in from inactivation to more negative potentials,
blocker SA and AV nodes
thereby tending to increase refractoriness
- Whether a given drug exacerbates or suppresses
reentrant arrhythmias depends on the balance
between its effects on refractoriness and on
conduction in a particular reentrant circuit.
Na+ Channel Block (Na+ CB) - Na+ Channel Blocker Toxicity:
o Na+ channel blockade >> decreased
- The extent of blocking depends on:
conduction velocity >> slows atrial flutter rate >>
o heart rate (HR)
AV node permits a greater # of impulses to
o membrane potential
penetrate the ventricle (due to vagolytic
o drug-specific physiochemical characteristics
properties) >> increased HR
that determine T-recovery
o slowed conduction allows the reentrant
wavefront to persist within the tachycardia
circuit
o (e.g., procainamide and quinidine) have been
reported to exacerbate neuromuscular
paralysis by D-tubocurarine

SUBGROUP OF Na+ CHANNEL BLOCK

CLASS IA: Procainamide, Quinidine, & Disopyramide
- This change in threshold probably cause the NA+ - Drugs with local anesthetic action block sodium
CBs to:
channels and reduce the sodium current, INa.
o Increase both pacing threshold
- Oldest group of antiarrhythmic drugs and are still
o Increase the energy required to defibrillate
widely used
the fibrillating heart
- Na+ CB decreases conduction velocity in non-
PROCAINAMIDE
nodal tissue and increases QRS duration
Characteristic:
o Flecainide = prolong QRS intervals by 25%
- An analogue of the local anesthetic procaine
o Lidocaine = increases QRS intervals only at
- Exerts electrophysiological effects similar to those
very fast HR
of quinidine but lacks quinidine’s vagolytic and α
- Drug effects on the PR interval is highly modified by
adrenergic blocking activity.
autonomic effects
- Better tolerated than quinidine when given IV
- Action potential duration is either unaffected or is
shortened by Na+ CB; some Na+ channel–blocking
Therapeutic use:
drugs do prolong cardiac action potentials but by
- IV infusion in acute therapy of many
other mechanisms, usually K+ channel block
supraventricular and ventricular arrhythmias.
- By increasing the pacing threshold, Na+ CB
- Long-term oral treatment is poorly tolerated and
decreases automaticity.
often is stopped owing to a/e

Mechanism of action & Pharmacologic effects:

- A blocker of open Na+ channels with an
intermediate T-recovery from block
- Effects:
o Prolongs cardiac action potentials in most
tissues; by blocking outward K+ current
o Decreases automaticity

Page 1 of 9
 o Increases refractory periods
o Slows conduction
- N-acetyl procainamide:
o The major metabolite
o lacks the Na+ channel–blocking activity of the
parent drug
o equipotent in prolonging action potentials.
o Plasma concentrations often exceed those of
procainamide
- It is the parent drug that slows conduction and
produces QRS interval prolongation.
- Hypotension may occur at high plasma
concentrations, usually due to ganglionic
blockade rather than to negative inotropic effect
Pharmacokinetics and Dosage
- Can be administered safely via IV and IM; well
absorbed orally
- The major pathway for hepatic metabolism is
conjugation by N-acetyl transferase to form N-
acetyl procainamide (NAPA)
- Elimination:
o Procainamide: eliminated rapidly (t ½ = 3–4 h)
by both renal excretion of unchanged drug
and hepatic metabolism; necessitates
frequent dosing or use of a slow-release
formulation
o NAPA: by renal excretion (t ½ = 6–10 h); not
significantly converted back to procainamide
- Dose adjustment:
o Both needed in pts w/ renal failure
o Reduction of dose and frequency; monitoring
needed
- If rapid procainamide effect is needed:
o IV loading dose of up to 12 mg/kg at a rate of
0.3 mg/kg/min or less rapidly
o Maintenance dosage of 2–5 mg/min, with
careful monitoring of plasma levels
- Ventricular arrhythmias: total dosage of 2–5 g/d is
usually required
Adverse Effects and Toxicity
- Hypotension & marked slowing of conduction are
major a/e of high concentrations (>10 μg/mL) esp
in IV
- Dose-related nausea is frequent during oral
therapy may be due to high plasma level of NAPA
- Torsades de pointes esp if plasma NAPA level >30
μg/mL
- Can produce potentially fatal bone marrow
aplasia in 0.2% of patients
- Procainamide-induced lupus syndrome:
o In individuals who are “slow acetylators”
o Develops more often and earlier during
treatment than among rapid acetylators
o During long-term therapy
o common early symptoms are rash and small-
joint arthralgias
o also includes pericarditis with tamponade,
can occur; renal involvement is unusual.
o resolve on cessation of therapy or during tx w/
NAPA
QUINIDINE
Characteristics and therapeutic use:
- A diastereomer of the antimalarial quinine
- Most potent of the antiarrhythmic substances
extracted from the cinchona plant
- Used to maintain sinus rhythm in patients with atrial
flutter or a-fib
- Used to prevent recurrence of v-tachycardia or VF
- May be useful in preventing recurrent VF in unusual
congenital arrhythmias syndromes (i.e., Brugada
syndrome or short QT syndrome)
Mechanism of action & Pharmacologic effects
- An open-state blocker of Na+ channels and
multiple cardiac K+ currents
- Has T-recovery in the intermediate (~3 sec) range
- Causes QRS to increase modestly (10-20%) at
therapeutic dosages
- Can prolong QT interval up to 25%
- At concen. of 1 μM, quinidine blocks Na+ current
and the rapid component of delayed rectifier (IKr)
- Higher concentrations block the ff:
o slow component of delayed rectifier
o inward rectifier
o transient outward current
o L-type Ca2+ current
- Blocking properties due to inc threshold for
excitability and decreased automaticity
- Due to K+ channel–blocking actions, it prolongs
action potentials in most cardiac cells, most
prominently at slow HR
- Consistently elicits EADs at slow HR in
midmyocardial cells and Purkinje cells
- Prolongs refractoriness in most tissues may be due
to both prolongation of action potential duration
and Na+ channel blockade
- Produces α adrenergic receptor blockade and
vagal inhibition:
o IV use is assoc w/ hypotension and sinus tachy
o vagolytic effects tend to inhibit its direct
depressant effect on AV nodal conduction;
can result in increased AV nodal transmission
of atrial tachycardias such as atrial flutter
Pharmacokinetics and Dosage
- Well-absorbed
- 80% bound to plasma proteins, including albumin
and the acute-phase reactant α1-acid
glycoprotein
- Greater-than-usual dose required in high-stress
states such as acute myocardial infarction.
- Undergoes extensive hepatic oxidative
metabolism
- ~20% is excreted unchanged by the kidneys.
- 3-hydroxyquinidine, a metabolite:
o Nearly as potent as quinidine in blocking
cardiac Na+ channels and prolonging cardiac
action potentials.
o unbound 3-hydroxyquinidine concent. equal to
or > than quinidine is tolerated by some
patients.
- Therapeutic plasma concentrations of 2 to 5 μg/mL
Adverse effects and Toxicity
Noncardiac
Page 2 of 9
- Diarrhea is the most common (30-50% of pts);
occurs within the first several days of quinidine
therapy but can occur later
- Diarrhea-induced hypokalemia may potentiate
torsades de pointes
- Thrombocytopenia; resolves rapidly with
discontinuation of the drug
- Hepatitis, bone marrow depression, and lupus
syndrome occur rarely; not r/t elevated plasma
quinidine concentrations
- Cinchonism: headache + tinnitus; r/t high plasma
quinidine concentration
Cardiac
- 2%–8% will develop marked QT interval
prolongation and torsades de pointes
- Quinidine-associated torsades de pointes
generally occurs at therapeutic or even
subtherapeutic plasma concentrations
- Resulting v-tach at high plasma concentrations
when high doses are used to convert a-fib to
normal rhythm (abandoned approach)
- Can exacerbate heart failure or conduction
system disease
- Tolerated in some pts w/ congestive heart failure
probably due to vasodilating actions
Drug Interactions
As a potent inhibitor of CYP2D6:
- Codeine = failure to form active metabolite
morphine results in decreased analgesia.
- Propafenone = results in elevated plasma
propafenone concentrations and increased β
adrenergic receptor blockade.
- Reduced clearance of digoxin; inhibition of P-
glycoprotein–mediated digoxin transport has been
implicated
- Dextromethorphan + very low-dose quinidine (30
mg) inhibits the first-pass metabolism of
dextromethorphan = higher systemic
concentrations than monotherapy; approved for
use in tx for pseudobulbar affect
Others:
- Quinidine metabolism is induced by drugs such as
phenobarbital and phenytoin
- Cimetidine and verapamil cause modest elevation
of plasma quinidine concentrations
DISOPYRAMIDE
Characteristics and Therapeutic use:
- Exerts electrophysiological effects very similar to
those of quinidine
- Can be used to maintain sinus rhythm in patients
with atrial flutter or a-fib
- Used to prevent recurrence of v-tach or VF.
- Because of its negative inotropic effects, it is
sometimes used in hypertrophic cardiomyopathy.
- Disopyramide is prescribed as a racemate.
Mechanism of action & Pharmacologic effects
- R-(–)-enantiomer produces similar (w/ quinidine)
Na+ channel block but does not prolong cardiac
action potentials
- Racemic disopyramide does not antagonize α
adrenergic receptors; exert prominent
anticholinergic actions that causes many of it’s a/e
Pharmacokinetics and Dosage
- Well absorbed
- Binding to plasma proteins is concentration
dependent
- Eliminated by both hepatic metabolism (to a
weakly active metabolite) and renal excretion of
unchanged drug
- Dose reduction needed in patients with renal
dysfunction.
- Higher-than-usual dosages may be required in
patients receiving drugs that induce hepatic
metabolism (ie. phenytoin)
Adverse effects and Toxicity
- Anticholinergic effects: precipitation of glaucoma,
constipation, dry mouth, and urinary retention
(latter is most common in males with prostatism but
also can occur in females)
- Torsades de pointes
- Depression of heart contractility:
o Can precipitate heart failure
o In patients with hypertrophic cardiomyopathy;
may be exploited to therapeutic advantage
to decrease dynamic outflow tract
obstruction
CLASS IB:Lidocaine & Mexiletine
- Rapidly associate and dissociate from sodium
channel
- Actions are manifested when the cardiac cell is
depolarized or firing rapidly
- Useful in treating ventricular arrhythmias
LIDOCAINE
Characteristics and Therapeutic Use
- A local anesthetic; useful in acute IV therapy of
ventricular arrhythmias
- Used for tx of pts w/ suspected myocardial
infarction; VF incidence is reduced
- Can cause lidocaine-exacerbated heart block or
congestive heart failure (no longer admin. routinely
in coronary care units)
Mechanism of Action & Pharmacologic effects
- Blocks both open and inactivated cardiac Na+
channels
- Recovery from block is rapid; exerts greater effects
in depolarized (e.g., ischemic) or rapidly driven
tissues.
- Not useful in atrial arrhythmias because compared
with diastolic (recovery) period, atrial action
potentials are so short and Na+ channel is in the
inactivated state only briefly
- Can hyperpolarize Purkinje fibers depolarized by
low [K]o or stretch; resulting increased conduction
velocity may be antiarrhythmic in reentry
- Decreases automaticity by reducing the slope of
phase 4 and altering the threshold for excitability
- Action potential duration usually is unaffected or is
shortened; may be due to block of the few Na+
Page 3 of 9
 channels that inactivate late during the cardiac
action potential.
- Usually exerts little to no significant effect on PR or
QRS duration
- Little effect on hemodynamic function
Pharmacokinetics and Dosage
- Well absorbed
- Undergoes extensive though variable first-pass
hepatic metabolism (not for oral use)
- IV route is preferred
- Metabolites are less potent: GX & monoethyl GX
o GX and lidocaine appear to compete for
access to the Na+ channel
o If GX accumulates, lidocaine’s efficacy may
be diminished
- With infusions >24 h, the clearance of lidocaine
falls; may be due to competition between parent
drug and metabolites for access to hepatic drug-
metabolizing enzymes.
- Plasma concentration and elimination in r/t
dosage:
o Decline biexponentially after a single IV dose
o Initial drop: t ½ of 8mins (the distribution from
the central compartment to peripheral tissues.
o Terminal elimination t ½ of ~2 h represents drug
elimination by hepatic metabolism
- Lidocaine’s efficacy depends on maintenance of
therapeutic plasma concentrations in the central
compartment; dosage should be..
o Loading dose = of 3-4 mg/kg over 20–30 min
(e.g., an initial 100 mg followed by 50 mg
every 8 min for three doses)
o Maintenance = 1 - 4 mg/min
- The time to steady-state lidocaine concentrations
is approximately 8–10 h.
- In heart failure: decrease the ff
o Central volume of distribution is decreased;
total loading dose should be decreased.
o rate of the maintenance infusion
- In hepatic disease:
o Drug clearance is also reduced during tx with
cimetidine or β blockers, and during
prolonged infusions.
o Frequent measurement of plasma lidocaine
concentration and dose adjustment needed;
remain within the therapeutic range (1.5 to 5
μg/mL)
- Lidocaine is bound to the acute-phase reactant
α1-acid glycoprotein.
o Acute myocardial infarction are associated
with increases in α1-acid glycoprotein and
protein binding
o Some patients require and tolerate higher-
than-usual total plasma lidocaine
concentrations to maintain antiarrhythmic
efficacy.
Adverse effects and Toxicity
- Large IV dose given rapidly = seizures
- If plasma level of drug rise slowly above
therapeutic range = tremor, dysarthria, and
altered levels of consciousness
- Nystagmus is an early sign of lidocaine toxicity
MEXILETINE
MOA, Pharmacologic effects, & Therapeutic Uses
- An analogue of lidocaine
- Modified to reduce first-pass hepatic metabolism
and permit chronic oral therapy
- Its electrophysiologic and antiarrhythmic actions
are similar to those of lidocaine.
- Approved for treating ventricular arrhythmias;
mexiletine+quinidine or sotalol may increase
efficacy while reducing a/e
Pharmacokinetics, Dosage, and Adverse Effects
- Mexiletine undergoes hepatic metabolism, which is
inducible by drugs such as phenytoin.
- T ½ is 8–20 hours and permits dose of 2-3x per day.
- Dosage: 600–1200 mg/d
- Adverse effects are dose-related: can be
minimized by taking the drugs with food
o tremor, blurred vision, and lethargy
o nausea
CLASS IC: Flecainide & Propafenone
FLECAINIDE
Characteristics and Therapeutic Use
- Effects thought to be caused by drug’s very long T-
recovery from Na+ channel block
- Suppression of DADs triggered by RyR2 Ca2+
release may also contribute to flecainide’s
antiarrhythmic effect.
- Treatment use:
o atrial fibrillation
o ventricular arrhythmias (i.e., sustained
ventricular tachycardia)
- The drug of choice for preventing arrhythmias in
CPVT patients uncontrolled by β blockers.
Mechanism of action & pharmacologic effects
- Blocks Na+ current & delayed rectifier K+ current (IKr)
- It also blocks Ca2+ currents
- Action potential duration:
o Shortened in Purkinje cells; owing to block of
late-opening Na+ channels
o Prolonged in ventricular cells; owing to block of
delayed rectifier current
- In atrial tissue: flecainide disproportionately
prolongs action potentials at fast rates
- Prolongs the duration of PR, QRS, and QT intervals
even at normal HR
- Also an open channel blocker of RyR2 Ca2+
release channels:
o prevents arrhythmogenic Ca2+ release from the
SR and hence DADs in isolated myocytes
o RyR2 channel block by flecainide targets
directly the underlying molecular defect in
patients with mutations in the RyR2 gene and
the cardiac calsequestrin gene
o May explain why flecainide suppresses
ventricular arrhythmias in patients with CPVT
refractory to β blocker therapy
Pharmacokinetics and Dosage
- Flecainide is well absorbed.
- T ½: (allows twice daily dosing)
o shorter with urinary acidification (10 h)
Page 4 of 9
 o urinary alkalinization (17 h)
- Elimination occurs by both renal excretion of
unchanged drug and hepatic metabolism to
inactive metabolites.
- Hepatic metabolism: mediated by the
polymorphically distributed enzyme CYP2D6. If
pathway is absent (mutation or drug interactions)
= renal excretion
- Renal dysfunction + lack of active CYP2D6 =
toxicity
- Flecainide is a racemate
- Some suggested to avoid plasma flecainide
concentrations >1 μg/mL to minimize the risk of
flecainide toxicity
- Usual dosage: 100–200 mg BID
Adverse effects and Toxicity
- Dose-related blurred vision is the most common
noncardiac adverse effect
- Can exacerbate congestive heart failure in
patients with depressed LV performance.
- Exacerbation of potentially lethal arrhythmias.
o most serious adverse
o iacceleration of ventricular rate in patients with
atrial flutter
o increased frequency of episodes of reentrant
ventricular tachycardia
o increased mortality in patients convalescing
from myocardial infarction
- Can cause heart block in patients with conduction
system disease
PROPAF ENONE
Characteristics and Therapeutic use
- A Na+ channel blocker with a relatively slow time
constant for recovery from block (
- Some data suggest that it blocks K+ channels.
- Its major electrophysiological effect is to slow
conduction in fast-response tissues.
- a racemate
- Propafenone prolongs PR and QRS durations.
- Chronic therapy with oral propafenone is used to
maintain sinus rhythm in patients with
supraventricular tachycardias, including a-fib;
- It can be used in ventricular arrhythmias,
- R-(−) propafenone blocks RyR2 channels; may be
an alternative to flecainide in CPVT
Pharmacokinetics and Dosage
- Well absorbed
- Eliminated primarily by CYP2D6- mediated hepatic
metabolism; t ½ of 5-7hrs
- Metabolites:
o under extensive first-pass hepatic metabolism to
5-hydroxy propafenone; equipotent to
propafenone as a Na+ channel blocker but
much less potent as a β adrenergic receptor
antagonist.
o metabolite, N-desalkyl propafenone, is formed
by non-CYP2D6–mediated metabolism; less-
potent blocker of Na+ channels and β
adrenergic receptors.
- CYP2D6 activity can be inhibited markedly by a
number of drugs, i.e. quinidine and fluoxetine.
- Plasma propafenone concen. >1 μg/mL are assoc.
w/ clinical effects of β adrenergic receptor
blockade, such as reduction of exercise heart rate.
- Dosage:
o Usual: 450–900mg/d in three divided doses.
o Patients with moderate-to-severe liver disease
should be reduced to approx. 20%–30% of the
usual dose, with careful monitoring.
- A slow-release formulation allows BID dosing.
Adverse effects and Toxicity
- Acceleration of ventricular response in patients
with atrial flutter
- Increased frequency or severity of episodes of
reentrant v-tach
- Exacerbation of heart failure,
- β adrenergic blockade i.e., sinus bradycardia and
bronchospasm
Beta Blockers (β Adrenergic Receptors Blocker)
- β blockers diminish phase 4 depolarization >>
depress automaticity >> prolong AV conduction =
decrease heart rate and contractility
- Useful in treating tachyarrhythmias caused by
increased sympathetic activity.
- Also used for atrial flutter and fibrillation and for AV
nodal reentrant tachycardia.
- Can prevent life-threatening ventricular
arrhythmias following a myocardial infarction.
- β blockers are effective in controlling arrhythmias
caused by Na+ channel blockers; may be due in
the slowing of HR >> decreases the extent of rate-
dependent conduction slowing by Na+ channel
block
- Adverse effects:
o Fatigue; bronchospasm; hypotension,
o Impotence; depression
o aggravation of heart failure; worsening of
symptoms owing to PVD
o masking of the sx of hypoglycemia in DM pts
o in arrhythmias due to sympathetic stimulation
(e.g., pheochromocytoma or clonidine
withdrawal), results to unopposed α-adrenergic
stimulation
▪ severe HTN
▪ α-adrenergic–mediated arrhythmias
[In such patients, arrhythmias should be treated with
both α and β blockers or with a drug such as labetalol
that combines α- and β-blocking properties. Abrupt
discontinuation of chronic β-blocker therapy can lead
to “rebound” symptoms, including hypertension,
increased angina, and arrhythmias; thus, β blockers are
tapered over 2 weeks prior to discontinuation of
chronic therapy]
NADOLOL
- A long-acting antagonist with equal affinity for β1
and β2 receptors.
- Devoid of both membrane-stabilizing and intrinsic
sympathomimetic activity.
- Relatively long t ½
Page 5 of 9
 - It can be used to treat hypertension and angina
pectoris.
- Unlabeled uses have included migraine
prophylaxis, parkinsonian tremors, and variceal
bleeding in portal hypertension.
- Many clinicians now favor nadolol when β
blockade is needed in congenital arrhythmias
(CPVT, LQTS)
Pharmacokinetics
- Very soluble in water; incompletely absorbed from
the gut; its bioavailability is about 35%.
- The low lipid solubility of nadolol may result in lower
concentrations of the drug in the brain.
- Not extensively metabolized; largely excreted intact
in the urine.
- T ½ = 20 h; is administered once daily.
- May accumulate in patients with renal failure, and
dosage should be reduced in such individuals
ACETABULOL
- β1-selective antagonist with some intrinsic
sympathomimetic and membrane-stabilizing
activity.
- Used to treat:
o Hypertension; ventricular and atrial cardiac
arrhythmias
o Acute myocardial infarction in high-risk patients,
and Smith-Magenis syndrome.
- The initial dose of acebutolol in HTN = 400 mg/d; it
may be given as a single dose, but two divided
doses may be required for adequate control of
blood pressure.
- Optimal responses usually occur with doses of 400–
800 mg per day (range 200–1200 mg)
- As effective as quinidine in suppressing ventricular
ectopic beats
Pharmacokinetics
- Administered orally (starting dose 200 mg twice daily
titrated up to 1200 mg/d)
- Well absorbed; undergoes significant first-pass
metabolism to an active metabolite, diacetolol,
which accounts for most of the drug’s activity.
- Overall bioavailability is 35%–50%.
- The elimination t ½ = 3 h; t ½ of diacetolol is 8–12 h
- Excreted largely in the urine.
- Has lipophilic properties and crosses the blood-brain
barrier. It has no negative impact on serum lipids
(cholesterol, triglycerides, or HDL).
PROPRANOLOL
- Interacts with β1 and β2 receptors with equal
affinity (nonselective)
- Lacks intrinsic sympathomimetic activity; does not
block α-receptors
- May be administered IV for the management of
life-threatening arrhythmias or to patients under
anesthesia:
o usual dose is 1–3 mg, administered slowly (<1
mg/min)
o with careful and frequent monitoring of blood
pressure, ECG, and cardiac
o If an adequate response is not obtained, a
second dose may be given after several mins
Pharmacokinetics
- Propranolol is highly lipophilic; almost completely
absorbed after oral admin
- Much of the drug undergoes first-pass metabolism;
only ~25% reaches the systemic circulation.
- The degree of hepatic extraction of propranolol
declines as the dose is increased.
- Bioavailability may be increased with food and
during long-term therapy
- Readily enters the CNS.
- Approx. 90% of the drug protein-bound
- Extensively metabolized, with most metabolites
appearing in the urine
o 4-hydroxypropranolol = some β adrenergic
antagonist activity
- Clearance may vary with hepatic blood flow and
liver disease; may change during the
administration of other drugs that affect hepatic
metabolism.
- Short T½ (~4 h), BID dosing
- Sustained-release formulations maintain
therapeutic concentrations in plasma throughout
a 24-h period.
- Dosage:
o Tx of HTN and angina = the initial oral dose of 40–
80 mg per day. The dose may then be titrated
upward until the optimal response is obtained.
ESMOLOL
- β1-selective antagonist with a rapid onset and a
very short duration of action.
- It has little if any intrinsic sympathomimetic activity
and lacks membrane-stabilizing actions.
- Given via IV; used when β blockade of short
duration is desired or in critically ill patients in whom
adverse effects of bradycardia, heart failure, or
hypotension may necessitate rapid withdrawal of
the drug.
- Commonly used in patients during surgery to
prevent or treat tachycardia and in the treatment
of supraventricular tachycardia.
- The onset and cessation of β receptor blockade
with esmolol are rapid; peak hemodynamic effects
occur within 6–10 min of administration of a loading
dose, and there is substantial diminution of β-
blockade within 20 min of stopping an infusion.
- AHA guidelines recommend against using esmolol
in patients already on β blocker therapy,
bradycardic patients, and patients with
decompensated heart failure, as the drug may
compromise their myocardial function
- Esmolol is generally tolerated well, but it is
associated with an increased risk of hypotension
that is rapidly reversible
Pharmacokinetics
- Given by slow IV injection.
- Because esmolol is used in urgent settings where
immediate onset of β blockade is warranted, the
dosage is…
o Partial loading dose (500 μg/kg over 1 min)
o Followed by continuous infusion of the drug
(maintenance dose of 50 μg/ kg/min for 4
min).
Page 6 of 9
[If an adequate therapeutic effect is not observed
within 5 min, the same loading dose is repeated,
followed by a maintenance infusion at a higher rate.
This may need to be repeated until the desired end
point (e.g., lowered heart rate or blood pressure) is
approached.]
- Hydrolyzed rapidly by esterases in erythrocytes
- T½ = 8 min.
- T½ of the carboxylic acid metabolite is 4hrs;
accumulates during prolonged infusion of esmolol;
very low potency as a β receptor antagonist (1/500
of the potency of esmolol); it is excreted in the urine
METOPROLOL
- β1-selective receptor antagonist that is devoid of
intrinsic sympathomimetic activity and membrane-
stabilizing activity.
- The β-blocker most widely used in the tx of cardiac
arrhythmias
- Compared to nonselective β-blockers, such as
propranolol, it reduces the risk of bronchospasm.
- Has been used to treat:
o Essential HTN; angina pectoris
o Tachycardia; heart failure, and vasovagal
syncope
o as secondary prevention after myocardial
infarction
o an adjunct treatment of hyperthyroidism, and
for migraine prophylaxis.
- Generally is contraindicated for the tx of acute
myocardial infarction in patients with:
o HR <45 bpm
o heart block greater than first-degree (PR interval
≥ 0.24 sec)
o SBP <100 mm Hg
o Moderate-to-severe heart failure
Pharmacokinetics
- Almost completely absorbed after oral
administration
- Bioavailability is relatively low (~40%) due to first-
pass metabolism.
- Only 10% of the administered drug is recovered
unchanged in the urine.
- T½ is 3–4 h, but can increase to 7–8 h in CYP2D6
poor metabolizers
- An extended-release formulation is available for
once-daily administration.
K+ Channel Block
- These drugs prolong action potentials, usually by
blocking K+ channels in cardiac muscle or by
enhancing inward current, eg, through Na+
channels.
- Blockade of K+ channels >> diminished the
outward potassium current during repolarization
- Increased action potential duration also increases
refractoriness
- K+ channel block produces a series of desirable
effects:
o reduced defibrillation energy requirement
o inhibition of VF owing to acute ischemia
o increased contractility
- Amiodarone and sotalol appear to be at least as
effective as drugs with predominant Na+ channel–
blocking properties in both atrial and ventricular
arrhythmias
Toxicity of Drugs That Prolong the Action Potential
- Can disproportionately prolong cardiac action
potentials and the QT interval when underlying HR
is slow and can cause torsades de pointes
- “reverse-use dependence”
AMIODARONE
Characteristics and Therapeutic use
- A structural analogue of thyroid hormone; some
antiarrhythmic effects & toxicity may be
attributable to interaction w/ nuclear TH receptors
- Highly lipophilic; concentrated in many tissues;
eliminated extremely slowly
- Uses:
o Oral or IV tx for serious ventricular arrhythmias
o Tx of supraventricular arrhythmias (i.e. a-fib)
o first-line drug for mgt of ventricular
tachycardia or VF causing cardiac arrest
- Blocks inactivated Na+ channels; relatively rapid
rate of recovery (time constant≈ 1.6 sec) from
block.
Pharmacologic effects:
- Decreased Ca2+ current and transient outward
delayed rectifier and inward rectifier K+ currents
- Noncompetitive adrenergic-blocking effect.
- Inhibition of abnormal automaticity
- Prolongs action potential duration.
- Prolongations of the PR, QRS, and QT intervals and
sinus bradycardia in chronic therapy.
- Prolongs refractoriness in all cardiac tissues by:
o Na+ channel block >> Decreased
conduction velocity
o K+ channel block >> delayed repolarization
o Inhibition of cell-cell coupling
Pharmacokinetics and Dosage
- Oral bioavailability = 30%
- Heart tissue-to-plasma concentration ratios > 20:1
- Lipid-to-plasma ratios > 300:1
- Increases in refractoriness require several weeks to
develop
- Undergoes hepatic metabolism by CYP3A4 to
desethylamiodarone (metabolite w/ same effects)
- When withdrawn after years of use, plasma
concentrations decline with a T½ of wks to mos
- Therapeutic plasma concentration of 0.5- 2 μg/mL
- Dosage:
o High-dose oral loading regimen (e.g., 800 to
1600 mg/d) for several weeks before
maintenance therapy
o Maintenance dose:
▪ If presenting arrhythmia is life threatening =
>300 mg/d unless toxicity occurs.
▪ 200 mg/d or less = recurrence of an
arrhythmia would be tolerated
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- Dosage adjustments not required in hepatic, renal,
or cardiac dysfunction.
- Potently inhibits the hepatic metabolism or renal
elimination of many compounds.
o inhibition of CYP3A4, CYP2C9, and P-
glycoprotein
- Dosages of warfarin, other antiarrhythmics (e.g.,
flecainide, procainamide, and quinidine), or
digoxin usually require reduction during
amiodarone therapy.
Adverse effects and Toxicity
- Hypotension due to vasodilation and depressed
myocardial performance in IV form amiodarone
- A/e are unusual during oral drug-loading regimens
- Occasional pts develop nausea during the loading
phase, which responds to a dec in daily dose.
- Pulmonary fibrosis:
o most serious a/e during chronic tx
o progressive and fatal
o risk factors: Underlying lung disease, doses of 400
mg/d or more, and recent pulmonary insults
- With low doses, such as 200 mg/d or less as used
in atrial fibrillation, pulmonary toxicity is less
common
- Other a/e during long-term therapy:
o Corneal microdeposits
o hepatic dysfunction
o peripheral neuropathy
o photosensitivity
o hypo- or hyperthyroidism
- Despite the marked QT prolongation and
bradycardia, torsades de pointes and other drug-
induced tachyarrhythmias are unusual.
because sotalol is eliminated by renal excretion of
unchanged drug.
- The other a/e of sotalol therapy are those assoc.
with β adrenergic receptor blockade.
IBUTILIDE
- Ibutilide is an I-Kr blocker
- Also activates an inward Na+ current
- action potential–prolonging effect
- Administered as a rapid infusion (1 mg over 10 min)
for the immediate conversion of a-fib or flutter to
sinus rhythm.
- The drug’s efficacy rate:
o atrial flutter (50%-70%)
o atrial fibrillation (30%–50%)
- In a-fib, the conversion rate is lower in those in
whom the arrhythmia has been present for weeks
or months compared with those in whom it has
been present for days.
- The major toxicity with ibutilide is torsades de
pointes (6% of patients); requires immediate
cardioversion in up to one-third of these.
- The drug undergoes extensive first-pass
metabolism, so it is not used orally.
- It is eliminated by hepatic metabolism and has a
T½ of 2–12 h (average 6 h)
DOFETILIDE

SOTALOL
- Nonselective β adrenergic receptor antagonist
- Prolongs cardiac action potentials by inhibiting
delayed rectifier and possibly other K+ currents
- Prescribed as a racemate; the l-enantiomer is a
much more potent β adrenergic receptor
antagonist than the d-enantiomer, but the two are
equipotent as K+ channel blockers.
- In the U.S., sotalol is approved for use in patients
with both ventricular tachyarrhythmias and a-fib or
flutter.
- Prolongs action potential duration throughout the
heart and QT interval on the ECG.
- Effects of blocking both K+ channels and β
adrenergic receptors:
o decreases automaticity
o slows AV nodal conduction
o prolongs AV refractoriness; no effect on
DRONEDARONE
conduction velocity in fast-response tissue
- Sotalol causes EADs and triggered activity in vitro
and can cause torsades de pointes, especially
when the serum K+ concentration is low.
- Unlike the situation with quinidine, the incidence
of torsades de pointes seems to be dose-
dependent; torsades de pointes is the major
toxicity with sotalol overdose.
- Torsades de pointes occasionally occur at low
dosages, often in patients with renal dysfunction,

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Resources:
Goodman and Gillman
Lipincott

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