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Antiarrhythmic andAnticoagulant

https://t.me/medicina_free

Agents

CraigJ.Beavers

Anticoagulation Therapy

As outlined in the atrial brillation section (Chap.

9), one of the core goals in management is to pre-

vent or reduce the risk of stroke and systemic embolism. The preferred strategy to decrease risk is systemic anticoagulation. The Atrial Arrhythmia chapter will provide the recommendations of when and to whom anticoagulation therapy should be prescribed. However, as with

the antiarrhythmic agents, it is important to select the agent that optimizes efcacy and reduces risk of bleeding. Decisions should be made based on patient factors including renal function, liver function, weight, age, ability to adhere to regimen, cost, and other factors. In addition, the patient should have education provided about their anticoagulation at each encounter including benets and risks (Tables 7.1 and 7.2).

C. J. Beavers (*) University of Kentucky College of Pharmacy, Lexington, KY, USA e-mail: cjbeav2@uky.edu

https://doi.org/10.1007/978-3-031-35819-7_7

https://t.me/medicina_free

Non-cardiovascular

events

Phosphene

(transient enhanced

Cardiovascular

adverse events

Bradycardia,

hypertension,

Common dose(s)

in adults

Oral: 5mg twice

daily;

Pharmacokinetic

parameters

Distribution 2h;

brightness in limited

area of visual eld,

halos, image

decompositions,

colored bright

lights, or multiple

atrial brillation

maintenance:

7.5mg twice

daily

effective ~6h

Bioavailability:

~40%

Metabolism:

Extensively

intestinal and

images; occurs in

rst 2months and

most cases resolve

with

discontinuation).

hepatic via

CYP3A4

(CYP3A4 substrate)

Excretion: Feces

and urine (~4% has

C. J. Beavers

unchanged drug)

Example

drug(s)

Corresponding

likely therapeutic

mechanisms

Major clinical

applications

Electrophysiological

effects

Pharmacological

Table 7.1 Antiarrhythmic agents

targets

Ivabradine Half-life:

Reduced in SAN

automaticity

Potential new off

label applications

for

Inhibition of I

reducing the

sino-atrial node

Class 0: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers

HCN channel

mediated

pacemaker current

tachyarrhythmias

(e.g. inappropriate

sinus tachycardia;

not atrial

brillation [AF])

(SAN) phase 4

pacemaker

depolarization rate

(decreased

automaticity)

) block

7 Antiarrhythmic andAnticoagulant Agents

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Non-cardiovascular

events

Thrombocytopenia,

cinchonism, pruritis,

rash

Cardiovascular

adverse events

QRS

prolongation

with toxic

doses, torsades

de pointes (not

dose related)

Monitoring:

ECG as needed,

at least every

6months

Common dose(s)

in adults

Pharmacokinetic

parameters

Bioavailability:

>80%

Metabolism:

Substrate: CYP2C9

(minor), CYP2E1

(minor), CYP3A4

(major),

P-glycoprotein

(Pgp; minor)

Inhibits: CYP2D6

Anticholinergic

(contraindicated in

narrow-angle

Heart failure

exacerbations;

torsades de

Oral: 100–

200mg every 6h

(strong) CYP3A4

(weak), Pgp

Excretion: Urine

Bioavailability:

>80%

glaucoma); dry

mouth; urinary

retention;

constipation, blurry

vision

pointes

Monitoring:

ECG as needed,

at least every

6months

Metabolism:

Extensively

intestinal and

hepatic via

CYP3A4

Limited with

intravenous use

Hypotension,

cardiac

arrhythmias,

heart failure

IV: 10–17mg/kg

(ideal body

weight) at a rate

of 20–50mg/min

Bioavailability: Not

applicable given

(CYP3A4 substrate)

Excretion: Urine

intravenous

exacerbation

Monitoring:

Telemetry

or 100mg every

5min;

maintenance

infusion: 1–6mg/

administration

Metabolism

Substrate: CYP2D6

(minor)

(continued)

min

Excretion: Urine

Example

drug(s)

Quinidine Half-life: 4–10h

Corresponding

likely therapeutic

mechanisms

Reduction in

Major clinical

applications

Supraventricular ,

Electrophysiological

Pharmacological

Reduction in peak I

effects

Class Ia: Voltage-gated Na+channel blockers

Nav 1.5 open state,

targets

ectopic ventricular/

atrial automaticity;

reduction in

accessory pathway

conduction;

tachyarrhythmias,

particularly

recurrent AF;

ventricular

tachycardia,

action potential (AP)

generation, with

increased excitation

threshold

intermediate

dissociation

kinetics; often

concomitant K+

channel block

increase in

refractory period,

decrease reentrant

tendency

ventricular

brillation

(including short

QT syndrome

[SQTS] and

Brugada

syndrome)

Disopyramide Half-life: 4–10h

Procainamide Half-life: 3–4h

https://t.me/medicina_free

Non-cardiovascular

events

Dizziness,

nervousness,

Cardiovascular

adverse events

Bradycardia,

cardiac

Common dose(s)

in adults

Intravenous (IV):

1–1.5mg/kg

Pharmacokinetic

parameters

Bioavailability: Not

unsteady gait,

gastrointestinal

distress, nausea,

vomiting, tremor

arrhythmia

Monitoring:

Telemetry

bolus, repeat at

0.5–0.75mg/kg

every 5–10min

(up to 3mg/kg);

follow with

applicable due

intravenous

administration

Metabolism:

Substrate: CYP1A2

continuous

infusion at

1–4mg/min)

(major), CYP2A6

(minor), CYP2B6

(minor); CYP2C9

(minor), CYP3A4

(major)

Excretion: Urine

Dizziness,

nervousness,

unsteady gait,

gastrointestinal

distress, nausea,

Exacerbation of

cardiac

arrhythmia

Monitoring:

ECG as needed,

Oral: 150–

200mg every

8–12h; adjust

dose as needed in

50–100mg

Bioavailability:

>80%

Metabolism:

Substrate: CYP1A2

vomiting, tremor

at least every

6months

increments no

more frequently

than every

2–3days up to

300mg every

8–12h

(major), CYP2D6

(major)

Inhibits: CYP1A2

(moderate)

Excretion: Urine

C. J. Beavers

Example

Corresponding

likely therapeutic

Major clinical

Electrophysiological

Pharmacological

Table 7.1 (continued)

drug(s)

Lidocaine Half-life: 120min

mechanisms

Reduction in

applications

Ventricular ,

effects

Reduction in peak I

Class Ib: Voltage-gated Na+ channel blockers

Nav 1.5 open state;

targets

ectopic ventricular

automaticity;

reduction in

delayed

afterdepolarization

(DAD) induced

tachyarrhythmias

(ventricular

tachycardia,

ventricular

brillation),

particular after a

AP generation with

increased excitation

threshold

window current

rapid dissociation;

triggered activity;

reduced reentrant

tendency by

converting

myocardial

infarction

Mexiletine Half-life: 9–15h

unidirectional

block, particularly

in ischemic,

partially

depolarized

myocardium

7 Antiarrhythmic andAnticoagulant Agents

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Non-cardiovascular

events

Metallic taste,

dizziness

Cardiovascular

adverse events

Atrial utter

with 1:1

conduction,

ventricular

tachycardia,

may unmask

Brugada-type

ST elevation,

contraindicated

with coronary

disease

Common dose(s)

in adults

Oral:

Immediate

release: 150mg

every 8h with

increase every

3–4days up to

300mg every 8h;

450mg once for

pill in pocket

dosing

Extended release:

Pharmacokinetic

parameters

Bioavailability:

>80%

Metabolism:

Substrate: CYP1A2

(minor), CYP2D6

(major), CYP3A4

(major)

Inhibits: CYP1A2

(weak), CYP2D6

(weak); P-gp

Monitoring:

ECG as needed,

at least every

6months

225mg every

12h; dose may

increase every

5days up to

Excretion: Urine

425mg every

12h

Dizziness,

headache, visual

blurring

Atrial utter

with 1:1

conduction,

ventricular

Oral: 50–300mg/

day in divided

doses 8–12h (can

go up to 400mg

Bioavailability:

>80%

Metabolism:

tachycardia,

may unmask

Brugada-type

ST elevation,

contraindicated

with coronary

for ventricular

arrhythmias

management)

Substrate CYP1A2

(minor) and

CYP2D6 (major)

Excretion: Urine

with some fecal

disease

Monitoring:

ECG as needed,

at least every

6months

(continued)

Example

drug(s)

Propafenone Half-life: 9–15h

Corresponding

likely therapeutic

mechanisms

Reduction in

Major clinical

applications

Supraventricular

effects

targets

Class 1c: Voltage-gated Na+ channel blockers

Reduction in peak I

Nav 1.5 inactivated

Electrophysiological

Pharmacological

ectopic ventricular/

atrial automaticity;

reduction in

DAD-induced

tachyarrhythmias

(atrial tachycardia,

atrial utter, atrial

brillation, and

AP generation and

with increase

excitation threshold

state; slow

dissociation

triggered activity;

reduced reentrant

tendency by

converting

tachycardias

involving

accessory

pathways);

unidirectional

block to

bidirectional block;

slowed conduction

ventricular

tachyarrhythmias

resistant to other

treatment in the

Flecainide Half-life: 10–18h

and reduced of

excitability

particularly at

rapid heart rates

blocking reentrant

absence of

structural heart

disease, premature

ventricular

contraction,

pathways showing

depressed

conduction

catecholaminergic

polymorphic

ventricular

tachycardia

https://t.me/medicina_free

Non-cardiovascular

events

Dizziness,

headache,

Cardiovascular

adverse events

Bradycardia,

hypotension,

Common dose(s)

in adults

Oral: 500 to

1000mg twice

Pharmacokinetic

parameters

Bioavailability:

constipation

prolonged QT

Monitoring:

ECG as needed,

at least every

daily, may

increase to

1000ng twice

daily as needed

>76%

Metabolism:

Substrate: CYP2D6

(minor), CYP3A4

6months, renal

function

(major), P-gp

(minor)

Inhibits: CYP2D6

(weak), CYP3A4

(weak), P-gp

C. J. Beavers

Excretion: Urine

Example

Corresponding

likely therapeutic

Major clinical

Electrophysiological

Pharmacological

Table 7.1 (continued)

drug(s)

Ranolazine Half-life: 7h

mechanisms

Decrease AP

recovery time;

reduction in early

applications

Ventricular

tachycardia, as a

potential new class

) affecting

effects

targets

current (I

AP recovery,

Class 1d: Voltage-gated Na+ channel blockers

Nav 1.5 late current Reduction in late Na+

afterdepolarization

(EAD) induced

triggered activity

of drugs for the

management of

tachyarrhythmias

refrac4toriness,

repolarization

reserve, and QT

interval

7 Antiarrhythmic andAnticoagulant Agents

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Non-cardiovascular

events

Cardiovascular

adverse events

Common dose(s)

in adults

Pharmacokinetic

parameters

Dizziness, fatigue

Bradycardia,

hypotension

Monitoring:

Blood pressure

and heart rate

Refer to drug

reference/package

insert for each

agent’s dosing

information

Refer to drug

reference/package

insert for each

agent’s

pharmacokinetic

information

Note: atenolol is

cleared renally and

should be avoided

in patient with renal

(continued)

disease

Example

drug(s)

Corresponding

likely therapeutic

mechanisms

Major clinical

applications

Electrophysiological

effects

Class II: Autonomic inhibitors and activators

targets

Class IIa

Pharmacological

Non-selective

β inhibitors:

Carvedilol,

propranolol,

nadolol.

Selective

Reduction in SAN

automaticity;

reduction in AVN

automaticity;

reduction in

ectopic ventricular/

Sinus tachycardia

or other types of

tachycardic,

including

supraventricular

(atrial brillation,

Inhibition of

adrenergically

induced G

protein-mediated

effects of increased

adenylyl kinase

Non-selective

β- and selective

β1-adrenergic

receptor inhibitors

β1-adrenergic

inhibitors:

Atenolol,

bisoprolol,

betaxolol,

esmolol,

atrial automaticity;

reduction in EAD-/

DAD- induced

triggered activity;

reduced SAN

reentry; reduction

atrial utter, atrial

tachycardia),

arrhythmias; rate

control of atrial

brillation and

ventricular

activity and cyclic

AMP with effects of

including slowed

SAN pacemaker rate

metoprolol

(tartrate and

succinate)

in AVN conduction

terminating reentry

tachyarrhythmias

(ventricular

tachycardia,

premature

ventricular

contraction)

Note: Atenolol,

propranolol, and

nadolol used in

long QT syndrome;

nadolol used in

catecholaminergic

polymorphic

ventricular

tachycardia

https://t.me/medicina_free

Non-cardiovascular

events

Flushing, dizziness,

headache,

Cardiovascular

adverse events

Cardiac

arrhythmias,

Common dose(s)

in adults

Intravenous:

2–10mcg/min IV;

Pharmacokinetic

parameters

Bioavailability: Not

hypokalemia

hypertension

Monitoring:

Heart rate,

blood pressure,

potassium

titrate to patient

response

applicable due to

intravenous

administration

Metabolism: None

Excretion: Urine

Hyperthermia,

dizziness,

confusion,

electrolytes

Cardiac

arrhythmias

Monitoring:

Heart rate,

Intravenous,

intramuscular:

0.5–1mg every

3–5min; 1mg

Bioavailability: Not

applicable due to

intravenous

abnormalities

blood pressure,

electrolytes,

mental status

preferred for

severe

bradyarrhythmia;

maximum total

dose 3mg

administration

Metabolism: None

Excretion: Urine

C. J. Beavers

Example

Corresponding

likely therapeutic

Major clinical

Electrophysiological

Pharmacological

Table 7.1 (continued)

drug(s)

Isoproterenol Half-life: 2.5–5min

mechanisms

Increase escape

Accelerating rates

applications

Activation of

effects

Class IIb

Non-selective

targets

ventricular

automaticity;

suppression of

Brady-cardia

of ventricular

escape rhythm in

cases of complete

atrioventricular

-protein

adrenergically

induced G

effects of increasing

adenylyl kinase

β-adrenergic

receptor activators

dependent

EAD-related

triggered activity

block before

denitive

pacemaker

implantation;

acquired,

activity and cAMP;

decrease in RR and

PR intervals

Atropine Half-life: 3–4h

Increase in SAN

often-drug related,

bradycardia-

dependent torsades

Mild or moderate

de pointes

Inhibition of

Class IIc

Muscarinic M

automaticity;

increase in AVN

conduction

symptomatic sinus

bradycardia;

supra-His, AVN,

conduction block,

elg. In vagal

syncope or acute

supraventricular

(SAN, atrial, AVN)

muscarinic M

cholinergic receptors;

decrease RR and PR

intervals

receptor inhibitors

inferior myocardial

infarction

7 Antiarrhythmic andAnticoagulant Agents

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Non-cardiovascular

events

Digoxin toxicity

(nausea, vomiting,

visual disturbances

[yellow, blurred

vision, halos],

lethargy,

arrhythmias, worse

with hypokalemia)

Cardiovascular

adverse events

Cardiac

arrhythmias

Monitoring:

Heart rate,

blood pressure,

electrolytes,

digoxin level,

serum creatinine

Common dose(s)

in adults

Oral: 0.125–

0.25mg daily

Intravenous:

0.25–0.5mg over

several min, with

a repeat dose of

0.35mg every 6h

to a maximum

dose of 1.5mg

over 24h

Pharmacokinetic

parameters

Bioavailability:

70–85%

(formulation

dependent)

Metabolism:

Substrate: CYP3A4

(minor), P-gp

Excretion: Urine

Headache,

dizziness, facial

ushing,

gastrointestinal

Cardiac

arrhythmia,

chest pressure

Monitoring:

Intravenous:

Initial 6mg IV

push (rapid, with

20mL saline

Bioavailability: Not

applicable

Metabolism: None

distress, neck

discomfort, dyspnea

ECG, heart rate,

blood pressure

ush); if not

effective within

1–2min, 12mg

maybe given; may

repeat 12mg

bolus if needed.

Maximum single

dose 12mg. Note:

Initial dose

should be reduced

to 3mg if patient

is currently

receiving

carbamazepine or

dipyridamole, has

a transplanted

heart or if

adenosine

administered via

(continued)

central line

Example

drug(s)

Digoxin Half-life: 38h

Corresponding

likely therapeutic

mechanisms

Reduction in SAN

Major clinical

applications

Sinus tachycardia

Electrophysiological

effects

Activation of

Class IId

targets

Muscarinic M

Pharmacological

automaticity;

reduced SAN

or supraventricular

tachyarrhythmias

supraventricular

(SAN, atrial, AVN)

receptor activators

reentry; reduction

in AVN conduction

terminating reentry

muscarinic M

cholinergic receptors

activates K channels,

hyperpolarizing the

SAN and shortening

APDs in atrial and

Adenosine Half-life: <10s

Reduction in SAN

automaticity;

Acute termination

of AVN

Activation of

AVN tissue

adenosine A

Class IIe

Adenosine A

receptor activators

reduction in AVN

conduction,

terminating

tachycardia and

cAMP mediated

triggered VTs;

receptors in

supraventricular

tissue (SAN, atrial,

reentry; reduction

in EAD-/DAD-

induced triggered

activity

differentiation of

sinus versus atrial

tachycardia

KAdo

AVN) activates G

channels and I

protein-coupled

inward rectifying K

current

hyperpolarizing the

SAN and shortening

APDs in atrial and

AVN tissue

https://t.me/medicina_free

Non-cardiovascular

events

Cardiovascular

adverse events

Common dose(s)

in adults

Pharmacokinetic

parameters

Pulmonary (acute

Sinus

Supraventricular

hypersensitivity

pneumonitis,

chronic interstitial

inltrates);

bradycardia,

QTc

prolongation,

cardiac

arrhythmias

Intravenous:

150mg over

10min, then

40–55days

Bioavailability:

35–65%

Metabolism:

hepatitis; thyroid

(hypothyroid or

hyperthyroid):

Photosensitivity;

blue-grey skin

discoloration with

arrhythmias

Monitoring:

Blood pressure,

heart rate, ECG,

history and

physical exam

1mg/min for 6h,

then 0,5mg/min

for 18h. Continue

for a total load up

to 10g; may

nish load with

Substrate: CYP1A2

(minor), CYP2C19

(minor), CYP2C8

(minor), CYP2D6

(minor), CYP3A4

(major), P-gp

chronic high doses;

nausea; ataxia;

tremor; alopecia

every

3–6months,

pulmonary

function test,

chest X-ray

every

oral dosing.

Oral: 600–

800mg daily in

divided doses for

a total of 10g

load then

(minor)

Inhibitor: CYP2C9

(weak), CYP2D6

(weak), CYP3A4

(weak), P-gp

Excretion: Feces

3–6months,

liver function

test baseline and

semiannually;

electrolytes,

maintenance of

200–400mg once

daily

Ventricular

arrhythmias:

thyroid function

tests before

treatment and

periodically

thereafter

Intravenous:

150mg over

10min, then

1mg/min for 6h,

then 0,5mg/min

C. J. Beavers

(3–6months);

regular

ophthalmic

exams

for 18h. Continue

for a total load up

to 10g; may

nish load with

oral dosing.

Oral: 400mg every

8–12h for 1–2

weeks, followed by

200–400 mg once

daily

Example

Corresponding

likely therapeutic

Major clinical

Electrophysiological

Pharmacological

Table 7.1 (continued)

drug(s)

mechanisms

applications

effects

targets

Amiodarone Half-life:

Increase in AP

recovery time;

increase in

refractory period

with decrease

reentrant tendency;

Ventricular

tachycardia in

patients without

structural heart

disease or with

channel blockers

Block of multiple K

channel targets

channel blockers and openers (note this table will focus on class IIIa; IIB or IIc not highlighted due to lack of currently approved agents at time of publication)

Class III: K

Class IIIa-voltage dependent K

channel blockers

Nonselective K

remote myocardial

resulting in prolonged

atrial, Purkinje, and/

or ventricular

myocyte AP recovery,

note: Amiodarone

also slows sinus

node rate and

atrioventricular

infarction

(amiodarone only)

tachyarrhyhtmias

with Wolff-

increased ERP, and

reduced

repolarization

reserve; prolonged

conduction (has

class II and IV

properties)

Parkinson white

syndrome; atrial

brillation with

atrioventricular

conduction via

QT intervals

accessory pathway

(amiodarone only);

ventricular

brillation and

premature

ventricular

contraction

(amiodarone only);

Tachyarrhyhtmias

associated with

supraventricular

arrhythmias and

atrial brillation

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