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7 Antiarrhythmic andAnticoagulant Agents

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Anorexia, nausea,

hepatotoxicity,

Non-cardiovascular

events

Cardiovascular

adverse events

Common dose(s)

in adults

Pharmacokinetic

parameters

pulmonary toxicity

Bradycardia,

new onset or

worsening heart

failure (death

Oral: 400mg

twice daily with

meals

Bioavailability:

Without food: 4%,

with high fat meal

increased in

patients with

symptomatic

heart failure),

15%

Metabolism:

Substrate: CYP3A4

(major)

prolonged QTc/

torsades de

pointes

Monitoring:

Inhibits: CYP2D6

(weak), CYP3A4

(moderate),P-gp

Excretion: Feces

ECG (at least

every

3months), heart

rate, blood

pressure, signs/

symptoms of

heart failure,

signs of

pulmonary

toxicity, liver

enzymes

(continued)

Dronedarone Half-life: 13–19h

Example

drug(s)

Corresponding

likely therapeutic

mechanisms

Major clinical

applications

Electrophysiological

effects

Pharmacological

targets

https://t.me/medicina_free

Headache,

Non-cardiovascular

Cardiovascular

Common dose(s)

Pharmacokinetic

dizziness, nausea

events

Torsades de

pointes

adverse events

Oral: Note CrCl

and QTc interval

in adults

(extended with renal

parameters

Monitoring:

ECG

monitoring,

baseline and

must be

determined prior

to rst dose. If

QTc>440ms

impairment)

Bioavailability:

>90%

Metabolism:

regular serum

creatine,

electrolytes

(>500ms in

patients with

ventricular

conduction

abnormalities),

doffetilide is

Substrate: CYP3A4

(major)

Excretion: Renal

contraindicated.

Adjust dose in

those with CrCL

<60mL/min.

Patient requires

hospitalization for

3days when

starting

Initial 500mcg

twice daily

(reduce dose

based on QTc and

CrCl; refer to

package insert)

C. J. Beavers

Example

Corresponding

likely therapeutic

Major clinical

Electrophysiological

Pharmacological

Table 7.1 (continued)

Dofetilide Half-life: ~ 10h

drug(s)

Increase in AP

recovery time;

mechanisms

applications

effects

targets

increase in

Ventricular

tachycardia in

patients without

Prolonged atrial,

Purkinje and

ventricular myocyte

1current

Kv11.1 (HERG)

channel-mediated

rapid K

refractory period

with decrease

reentrant tendency

structural heart

disease or with

remote myocardial

infarction (sotalol

only)

AP recovery, increase

ERP, and reduced

repolarization

reserve; prolonged

QT intervals

) blockers

tachyarrhyhtmias

with Wolff-

Parkinson white

syndrome; atrial

brillation with

atrioventricular

conduction via

accessory pathway

(sotalol only);

ventricular

brillation and

premature

ventricular

contraction (sotalol

only);

Tachyarrhyhtmias

associated with

supraventricular

arrhythmias1 and

atrial brillation

7 Antiarrhythmic andAnticoagulant Agents

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(continued)

Nausea

Non-cardiovascular

events

Torsades de

Cardiovascular

Common dose(s)

Pharmacokinetic

Example

pointes

adverse events

Intravenous:

<60kg: 0.01mg/

in adults

Bioavailability: Not

parameters

Ibutilide Half-life: 2–12h

drug(s)

kg over 10min

applicable

Brochospasm

Bradycadia,

torsades de

Note CrCl and

≥60kg: 1mg

Metabolism: None

QTc interval must

over 10min

Bioavailability:

Excretion: Urine

Sotalol Half-life: 12h

pointes

Monitoring:

ECG

monitoring,

baseline and

be determined

prior to rst dose.

If CrCl ≤ 60mL/

min, dose

adjustment

Well absorbed;

decreased by ~20%

by meals compared

to fasting

Metabolism: None

regular serum

creatine,

electrolytes,

heart rate

warranted. Please

see package

insert.

Oral: 80mg twice

daily

Excretion: Renal

Intravenous:

75mg infused

over 5h twice

daily

Corresponding

likely therapeutic

mechanisms

Major clinical

applications

Electrophysiological

effects

Pharmacological

targets

https://t.me/medicina_free

Non-cardiovascular

events

Cardiovascular

adverse events

Common dose(s)

in adults

Pharmacokinetic

parameters

Headache

Bradycardia,

Oral:

hypotension,

peripheral

edema

Monitoring:

Blood pressure,

Immediate release:

30mg four times

daily; increase as

needed to achieve

rate control; usual

(depending on

immediate or

extended release)

Bioavailability:

~40%

heart rate

doses 120–

480mg/day in 3–4

doses

Extended release:

Initial 120mg

Metabolism:

Substrate: CYP2C9

(minor), CYP2D6

(minor), CYP3A4

(major), P-gp

once daily or in 2

divided doses;

increase as

needed; usual

dose 120–

(minor)

Inhibits: CYP2D6

(weak), CYP3A4

(moderate)

Excretion: Urine

480mg/day

Intravenous:

Bolus dose:

C. J. Beavers

0.25mg/kg (actual

body weight) over

2min. If rate

control

insufcient after

15min a repeat

bolus dose of

0.35mg/kg can be

given

Continuous

infusion: Initial

5–10mg/h;

infusion rate

maybe increased in

5mg/h increments

every 10–15min

up to maximum of

15mg/h

Example

Corresponding

likely therapeutic

Major clinical

Electrophysiological

Pharmacological

Table 7.1 (continued)

drug(s)

mechanisms

applications

effects

targets

Diltiazem Half-life: 3–9h

Reduction in AVN

conduction,

terminating

reentry; reduction

in EAD-/

DAD-induced

Supraventricular

arrhythmias and

ventricular

tachycardia

without structural

heart disease; rate

channel blockers

current

), resulting in

Block Ca

inhibition of SAN

pacing, inhibition of

AVN conduction,

prolonged ERP,

(note this table will focus on class IVa; IVb, IVc,IVd, IVe not highlighted due to lack of currently approved agents at time of publication)

current

Class IV: Ca2

blockers

Class IVa: Surface membrane Ca

L-type Ca

triggered activity

control of atrial

brillation

increased AP

recovery time

7 Antiarrhythmic andAnticoagulant Agents

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Non-cardiovascular

events

Headache,

constipation

Cardiovascular

adverse events

Bradycardia,

hypotension,

peripheral

edema

Monitoring:

Blood pressure,

heart rate

Common dose(s)

in adults

Oral:

Immediate

release: Initial

40mg three to

four times daily;

increase as

needed to achieve

rate control;

maximum dose:

480mg/day in

3–4 doses

Extended release:

Pharmacokinetic

parameters

Bioavailability:

20–35%

Metabolism:

Substrate: CYP1A2

(minor), CYP2B6

(minor), CYP2C9

(minor), CYP3A4

(major), P-gp

(minor)

Inhibitor: CYP1A2

(weak), CYP3A4

120–180mg once

daily; maximum

daily dose 480mg

Intravenous:

Bolus dose:

5–10mg over

(moderate), P-gp

Excretion: Urine

2min if rate

control

insufcient after

15–30min a

repeat bolus dose

of 0.35mg/kg can

be given

Continuous

infusion: Initial

5mg/h; infusion

rate maybe

increased in

5mg/h

increments every

15–30min up to

maximum of

20mg/h

Example

drug(s)

Verapamil Half-life: 2–12h

Corresponding

likely therapeutic

mechanisms

Major clinical

applications

Electrophysiological

effects

Pharmacological

targets

AP-action potential; APD-action potential duration; AVN-atrioventricular node; CrCL- creatinine clearance; DAD-delayed afterdepolarization; EAD- early afterdepolarization;

ERP- effective refractory period; P-gp-P-glycoprotein SAN- sino-atrial node

Adapted from the references [1–3]

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C. J. Beavers

Factor Xa inhibition

Factor Xa

inhibition

Factor Xa

inhibition

inhibitor

15mg daily (CrCl 15–50mL/min)

30mg daily

(CrCl

5mg twice daily 60mg daily 20mg daily with evening meal

2.5mg twice daily

If at least two of

150mg twice

daily

75mg twice

daily (CrCL

15–50mL/min)

• Age ≥80

• Weight

≤60kg

SCr ≥1.5mg/dL

three criteria:

15–30mL/min)

Child-Pugh class B:

Avoid or use with caution

Child-Pugh class C:

Avoid use

Child-Pugh

class B: Avoid

or use with

caution

Child-Pugh

class C: Avoid

use

Avoid or use with

caution

Child-Pugh class

Avoid use

No adjustment Child-Pugh class

66% renal (one-half as inactive form)

50% renal;

also, bile, feces

fecal

P-gp P-gp and CYP3A4 P-gp P-gp and CYP3A4

Avoid use Avoid use Avoid use Avoid use

Not applicable 30mg daily Not applicable

min, avoid use or

reduce dose

Table 7.2 Oral anticoagulants used in stroke prevention for AF

Characteristic Warfarin Dabigatran Apixaban Edoxaban Rivaroxaban

Vitamin K antagonist Direct thrombin

Mechanism of

adjust to achieve INR 2–3

Consider starting doses of ≤2.5mg

daily if:

action

Standard dosing 5mg daily (avoid loading doses),

Renal

impairment

• Age ≥65

• Weight ≤70kg

Poor nutritional status

• Signicant hepatic disease

• Increase bleeding risk

dosing

• Known warfarin sensitivity

• Decompensated HF

Consider starting doses of ≤ 2.5mg

Hepatic

daily if:

• Age ≥65

• Weight ≤70kg

Poor nutritional status

impairment

dosing

• Signicant hepatic disease

• Increase bleeding risk

• Known warfarin sensitivity

• Decompensated HF

Time to peak 5–7days 1–3h 1–2h 1–2h 2–4h

Half-life (h) ~40h 8–15h 12h 10–14h 7–11h

Excretion Hepatic, primarily through CYP2C9 80% renal 25% renal, 75%

Metabolized CYP2C9, CYP1A2, CYP3A4,

CYP2C19

Consider higher starting dose, monitor

INR closely

P-gp and/or

strong CYP3A4

inducers

P-gp inhibitors Not applicable If CrCl <50mL/

7 Antiarrhythmic andAnticoagulant Agents

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clarithromycin

• No dose change needed with concomitant

potential risk

Andexanet alfa and prothrombin complex concentrate

Not applicable • Avoid use

change needed

with

concomitant

• No dose

Not applicable Avoid use

Consider lower starting dose, monitor

INR closely

clarithromycin

Monitor INR closely Not applicable Use with caution Not applicable If CrCl <80mL/min, avoid use unless benet justies

Andexanet alfa

and

prothrombin

complex

concentrate

and prothrombin

complex

concentrate

Idarucizumab Andexanet alfa

concentrate, or fresh frozen plasma

Dual P-gp and

strong CYP

inhibitors

Dual P-gp and

moderate

CYP3A4

inhibitors

Reversal strategy Vitamin K, prothrombin complex

Package inserts from https://www.nlm.nih.gov

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C. J. Beavers

References

1. Lei M, Lin W, Terrar D, Huang CL.Modernized clas-

sication of cardiac antiarrhythmic drugs. Circulation.

2018;138:1879–96.

2. Zimetbuam P. Antiarrhyhtmic drug therapy for atrial brillation. Circulation. 2012;125:381–9.

3. Package inserts from https://www.nlm.nih.gov.

Bradycardia

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HannahKibler andSharonVannoy

Sinus Node Dysfunction

Sinus node dysfunction (SND) is often used to describe abnormalities of impulse conduction originating from the Sinoatrial (SA) node. Degenerative changes in sinus node tissue occur throughout the lifespan and can lead to alterations in the generation or conduction of impulses, such as a prolonged pauses or sinus bradycardic episodes. Sinus node dysfunction is most common in individuals over 70 years of age. Sick sinus syndrome (SSS) refers to the symptomatic expression of sinus node dysfunction in patients resulting in fatigue, presyncope, syncope, dizziness, dyspnea, and other outward signs of cardiac output.

Tachycardia- bradycardia syndrome refers to a condition, when an individual has a co-morbid conduction abnormality resulting in a rapid atrial rate, such as atrial brillation, atrial utter, or other supraventricular tachycardia. Upon conversion from the tachycardia, the sinus node fails to efciently create an impulse resulting in a pause or bradycardia. Patients may or may not be symptomatic with the conversion pause or bradycardia which results.

H. Kibler · S. Vannoy (*) Atrium Health Wake Forest Baptist, Winston-Salem, NC, USA e-mail: hkibler@wakehealth.edu;

svannoy@wakehealth.edu

Sinus Bradycardia

In some individuals, including trained athletes, a heart rate below 50bpm is acceptable and a normal variant. Bradycardias can be noted as a manifestation of increased vagal tone, normal aging, and are common in the elderly population as a result of disease progression such as in hypothyroidism. Symptomatic bradycardia is due to reduced cardiac output, which is a function of stroke volume and heart rate. The need for intervention is determined by the presence of symptoms.

Sinus Pause

A sinus pause, or sinus arrest, is the failure of the sinus node to generate an atrial depolarization for a period of time, generally dened as 3seconds or longer between atrial contractions. Pauses can result from a block of the normal impulse from the sinoatrial tissue or due to failure of the sinus node to depolarize. Nocturnal pauses are commonly related to obstructive sleep apnea, which should be considered in the differential for assessment and in the treatment plan. Pauses are also more common in patients with tachycardiabradycardia syndrome occurring when the tachyarrhythmia terminates and the sinus node is in recovery. The presence of sinus pauses, in absence of symptoms, does not always warrant

https://doi.org/10.1007/978-3-031-35819-7_8

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Table 8.1 Causes of bradycardia

Medications Tissue disorders Metabolic Miscellaneous Antiarrhythmics

Beta blockers Calcium Channel blockers (non-dihydropyridine) Digoxin Interferon Lithium Methyldopa Opioids Risperidone Psychotropic meds Sympatholytics Illicit drugs Toxins

Goldberger etal. [1], Kusumoto etal. [2], Semelka and Gera [3]

Amyloidosis Cardiomyopathies Ischemic, non-ischemic, inltrative Connective tissue disease RA, SLE, scleroderma Hemochromatosis Sarcoidosis Degenerative brosis

Hyper/hypokalemia Hypocalcemia Hypothermia Hypoxia Ion channel dysfunction

H. Kibler and S. Vannoy

Acute MI Autonomic dysfunction Cardiac surgery CABG, TAVR, maze, valve Replacement, ablation Hypothyroidism Infection Lyme disease, typhoid fever Dengue fever, malaria Guillain-Barre Obstructive sleep apnea

intervention and can be associated with various physiologic and pathologic conditions as well as extrinsic factors including medications, electrolyte imbalance, increased vagal tone, and others (see Table 8.1). Frequent sinus pauses lasting longer than 3seconds and are symptomatic warrant consideration for pacing support.

Chronotropic Incompetence

Chronotropic incompetence is dened as the inability of the heart rate to adjust appropriately in concordance with increased physical activity or cardiovascular demand. Patients can present with fatigue, lightheadedness, dyspnea on exertion, or syncope associated with activity. Further criteria for diagnosis of chronotropic incompetence, which is well established, includes the failure of the individual to reach 80% of their maximum predicted heart rate at peak exercise. This can be evaluated with exercise stress testing on a treadmill or bicycle. It is important to thoroughly assess individuals in whom there is suspicion for chronotropic incompetence as the condition is also associated with increased risk of coronary artery disease and is seen in approximately one-third of individuals with congestive heart failure [4]. In these patients, pacemaker

implantation can provide symptom relief through rate responsive pacing (see Chap. 13).

Atrioventricular Blocks

A disturbance of impulse conduction between the atria and ventricles is known as atrioventricular (AV) block or heart block. This can occur if there is delayed conduction, intermittent loss of conduction, or complete loss of conduction from the atria to the ventricles. AV block/heart block is categorized based on the severity of the impulse conduction disturbance.The types of AV block will be addressed separately below.

First Degree AV Block (See Figs.8.1 and8.2)

First-degree heart block is dened as prolonged conduction from the atria to the ventricles with a PR interval greater than 200ms. This can be secondary to a conduction delay at the AV node and/ or the His-Purkinje system. The site of delay can be difcult to differentiate, though one clue is response to exercise. Increased sympathetic tone can increase conduction velocity in AV node

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