Antidysrhythmic drugs

Dr. Sanooz
 Antidysrhythmic drugs

• Outline the Vaughan Williams’ classification of

Antidysrhythmic drugs with examples
• Explain the mechanism of action of each classes of
Antidysrhythmic drugs
• List the clinical uses of each classes of Antidysrhythmic drugs
• Describe the pharmacokinetic properties of individual drugs in
each classes of Antidysrhythmic drugs
• List Antidysrhythmic drugs unclassified in the Vaughan
Williams’ system
 Cardiac glycosides

• List the general actions & adverse effects of cardiac glycosides

• Explain the mechanism of action of cardiac glycosides
• List the drugs that increase myocardial contractility
• Describe the pharmacokinetic properties & uses of the
following:
Digoxin
Amrinone
Milrinone
ELECTROPHYSIOLOGY OF NORMAL CARDIAC RHYTHM
 MECHANISMS OF ARRHYTHMIAS
• Cardiac arrhythmias result from alterations in the orderly
sequence of depolarization and repolarization in the heart
• Factors precipitate or exacerbate arrhythmias:
- Ischemia
- Hypoxia
- Acidosis or alkalosis
- Electrolyte abnormalities
- Excessive catecholamine exposure
- Autonomic influences
- Drug toxicity (eg, digitalis or antiarrhythmic drugs)
- Overstretching of cardiac fibers
- Presence of scarred or otherwise diseased tissue
 MECHANISMS OF ARRHYTHMIAS
(1) Disturbances in impulse formation
(2)Disturbances in impulse conduction
(3) Both
 Treatment modalities
• Pharmacological Management
• Nonpharmacological strategies
- Transcatheter radiofrequency or cryothermal
ablation, intraoperative cryoablation ,
implantable pacemakers and defibrillators
• Pharmacological therapy remains a valuable
tool for monotherapy or as adjunctive therapy
in combination with device therapy
 Pharmacological Therapy
Drugs that exert direct effects on cardiac cells by
- inhibiting the function of specific ion channels
or ion pumps
- Altering the autonomic input into the heart
 Vaughn-Williams system
• Four classes based on their predominant mechanism of action
 SPECIFIC ANTIARRHYTHMIC
AGENTS
Class 1 action is sodium channel blockade.
• Effects on the action potential duration (APD) and the kinetics
of sodium channel blockade.
• Drugs with class 1A action prolong the APD and dissociate
from the channel with intermediate kinetics;
• Drugs with class 1B action shorten the APD in some tissues of
the heart and dissociate from the channel with rapid kinetics;
• Drugs with class 1C action have minimal effects on the APD
and dissociate from the channel with slow kinetics.
• Class 2 action is sympatholytic. Drugs with this action
reduce β-adrenergic activity in the heart.
• Class 3 action manifests as prolongation of the APD.
Most drugs with this action block the rapid
component of the delayed rectifier potassium
current, I Kr .
• Class 4 action is blockade of the cardiac calcium
current. This action slows conduction in regions
where the action potential upstroke is calcium
dependent, eg, the SA and AV nodes.
 CLASS I
• Block the voltage gated sodium channel delaying phase 0 of the
action potential and thereby slow conduction velocity in the tissue.
• Act when the channel is either in the open or inactivated state
rather than in the resting state
• Sodium channel inhibition also prolongs the effective refractory
period of fast-response
• fibers by necessitating a more hyperpolarized membrane potential
(more negative) be achieved prior to a return of excitability.
• many class I drugs possess local anesthetic actions
• can depress myocardial contractile force
• class I drugs also suppress both normal Purkinje fiber and His
bundle automaticity
 Class I antiarrhythmic agents
Three groups:
(1) Class IA drugs slow the rate of rise of phase 0 (Vmax) of the
action potential and prolong the refractory period;
(2) Class IB drugs have a minimal effect on Vmax and the refractory period of healthy
myocardium while causing conduction block in diseased myocardium
(3) Class IC drugs cause a marked depression in the conduction velocity with minimal
effects on refractoriness in all cardiac tissue.
 Class IA
Quinidine
•First clinically used antiarrhythmic agents
•Now used sparingly due to high incidence of ventricular proarrhythmia
•Quinidine shares all of the pharmacological properties of quinine, including
anti-malarial, antipyretic and skeletal muscle relaxant actions.

Pharmacokinetics:
•Nearly complete oral bioavailability
•Onset of action within 1–3 hours
•Peak effect within 1–2 hours
•The plasma half-life is 6 hours
•Primarily hepatic metabolism.
•Therapeutic serum concentrations are 2– 4 μg/mL.
Clinical Uses
•The use of quinidine is limited by the poor side
effect profile and the availability of equally or
more efficacious agents.
•Used in combination with other agents such as
mexilitine for the control of ventricular
arrhythmias
•May be useful in the patients with short QT
syndrome
 Adverse Effects
Diarrhea, upper-gastrointestinal distress, light-headedness
relatively common adverse effects include fatigue, palpitations, headache, angina-
like pain, and rash.
These adverse effects are dose-related and reversible with cessation of therapy.
Thrombocytopenia may also occur.
The cardiac toxicity : AV and intraventricular block, ventricular tachyarrhythmias,
and depression of myocardial contractility.
Ventricular proarrhythmia with loss of consciousness- “quinidine syncope,”
Large doses of quinidine can produce- cinchonism(ringing in the ears, headache,
nausea, visual disturbances or blurred vision, disturbed auditory acuity, and
vertigo)
Larger doses can produce confusion, delirium, hallucinations, or psychoses.
Quinidine can also cause hypoglycemia
 Contraindications
Complete AV block with a junctional or idioventricular escape
rhythm
Congenital QT prolongation
Congestive heart failure
Hypotension

Drug Interactions:
Quinidine increases the plasma concentrations of digoxin,
requiring a downward adjustment in the digoxin dose.
 Procainamide
•Derivative of the local anesthetic agent Procaine
•longer half-life, does not cause CNS toxicity at therapeutic
plasma concentrations, and is effective orally
•Procainamide is effective in the treatment of
supraventricular, ventricular, and digitalis-induced
arrhythmias
•Its use is limited by its short serum half-life and frequent
side effects when used chronically.
•The ECG changes are similar to quinidine.
Pharmacokinetics:
•Highly bio-available (75%–95%)
•Onset of action of 5–10 minutes
•Peak response following an oral dose is 60–90 minutes
•Plasma half-life of 2.5–4.5 hours (6–8 hours for the
sustained release preparation)
•Metabolized hepatically
•50%–60% is excreted unchanged in the urine
•The primary metabolite Nacetylprocainamide (NAPA) is cardioactive with class III
properties and is eliminated unchanged in the urine.
 Clinical Uses

•Accessory pathway mediated tachycardia

•Atrial fibrillation of recent onset
•All types of ventricular dysrhythmia
•Combined with patient cooling for the treatment
of post-operative junctional ectopic tachycardia
Intravenous administration for Brugada syndrome has emerged as a
possible diagnostic test.
 Adverse Effects
Acute cardiovascular reactions to procainamide administration include
Hypotension, AV block, intraventricular block, ventricular
tachyarrhythmias, and complete heart block.
Long-term drug use may result in a clinical lupus like syndrome

Contraindications. Contraindications are similar to those for quinidine

Drug Interactions.
•Cimetidine inhibits the metabolism of procainamide.
•Simultaneous use of alcohol will increase the hepatic clearance of
procainamide.
•The simultaneous administration of quinidine or amiodarone may
increase the plasma concentration of procainamide.
 Class IB
Lidocaine
local anesthetic
blocks sodium channels, binding to channels in both the open
and inactivated state.
like other class 1B agents acts preferentially in diseased tissue
causing conduction block and interrupting reentrant tachycardias
 Electrophysiological Actions
SA node and atrium:
has no effect on the sinus rate and weak effects on atrial tissue.
AV node:
minimal effects on the conduction velocity and ERP of the AV node.
His-Purkinje system and ventricular muscle:
reduces membrane responsiveness and decreases automaticity.
in very low concentrations slows phase 4 depolarization in Purkinje fibers.
In higher concentrations, automaticity may be suppressed, and phase 4
depolarization eliminated.

Electrocardiographic Changes:
PR, QRS, and QT intervals are usually unchanged
QT interval may be shortened in some patients

At usual doses, lidocaine does not depress myocardial function, even in the face of
CHF.
 Pharmacokinetics
•extensive first pass metabolism, not used orally.
•onset of action is immediate
•plasma half-life of 1–2 hours
•Elimination primarily via liver (90%) with the rest unchanged in
the urine.
•Therapeutic serum levels range from 1.5–6.0 μg/mL.
•clearance is reduced by CHF, hepatic dysfunction, and
•concomitant treatment with cimetidine or beta-blockers.
Clinical Uses :
•Ventricular arrhythmias
•Lidocaine’s use has decreased as amiodarone is frequently
being used

Adverse Effects:
•CNS toxicity is the most frequent adverse effect.
•Paresthesias, disorientation, and muscle twitching, psychosis,
respiratory depression, and seizures.
•Myocardial depression at very high doses.
Contraindications:
hypersensitivity to local anesthetics of the amide type
severe hepatic dysfunction or a previous history of grand mal
seizures due to lidocaine.

Drug Interactions: The concurrent administration of lidocaine

with cimetidine
 Mexiletine

•Mexiletine is a structural analog of lidocaine altered to prevent

first pass metabolism.
•Mexiletine has properties similar to lidocaine and is frequently
combined with quinidine to increase efficacy while decreasing
the risk of pro-arrhythmia.
 Class IC
Flecainide
Flecainide slows conduction throughout the heart
most notable in the His- Purkinje system and ventricular
myocardium.
weakly inhibits the delayed rectifier potassium channel (slightly
prolonging repolarization) and inhibits abnormal automaticity.
 Electrophysiological Actions
SA node and atrium: insignificant decrease in heart rate.
In the atrium- decreases the conduction velocity, shifts the membrane
responsiveness curve to the right, and prolongs the action potential in a use-
dependent fashion.

AV node: Atrioventricular conduction is prolonged.

His-Purkinje system and ventricular muscle:

slows conduction in the His-Purkinje system and ventricular muscle to a greater
degree
than in the atrium.
cause block in accessory AV connections, which is the principal mechanism for its
effectiveness in treating atrioventricular reentrant tachycardia.

Electrocardiographic Changes:
increases the PR, QRS, and to a lesser extent, the QTc intervals.
Pharmacokinetics:
Well absorbed
bioavailability of 85%–90%.
Oral absorption may be inhibited by milk and milk-based formulas.
The onset of action is 1– 2 hours
serum half-life of 12–30 hours
primarily metabolized in the liver and excreted in the urine.
Therapeutic serumconcentrations are 0.2–1.0 μg/mL.
Clinical Uses:
•Atrial arrhythmias- particularly those supported by reentrant
mechanisms
•Life threatening ventricular arrhythmias
•the second-line drug after digoxin for therapy of fetal
arrhythmias
•second line drug for SVT in children who are not well controlled
on beta-blockers
- Used with caution in patients with congenital heart disease
Adverse Effects:
Most adverse effects are observed within a few days of initial drug
administration
dizziness, visual disturbances, nausea, headache,dyspnea , Worsening
of heart failure, prolongation of the PR and QRS intervals

Contraindications:
Preexisting second- or third-degree heart block.
cardiogenic shock

Drug Interactions: Cimetidine

 Propafenone

•Blocks the sodium channel

•Weakly blocks potassium channels
•Weak β-receptor antagonist and L-type calcium channel blocker
Electrophysiological Actions
SA node: sinus node slowing.
Atrium:
action potential duration and effective refractory period are prolonged
conduction velocity is decreased
slow atrial flutter to a rate that allows for more rapid conduction into
the ventricle.
AV node:
Intravenous administration slows conduction through the AV node.
His-Purkinje system and ventricular muscle:
slows conduction and inhibits automatic foci.

Pharmacokinetics:
nearly 100% absorbed following an oral dose
serum half-life of 2–10 hours
metabolized in the liver with nearly one-third of the drug excreted unchanged
in the urine
Therapeutic serum concentration 0.06–0.10 μg/mL.
Clinical Uses:
supraventricular arrhythmias
life threatening ventricular arrhythmias in the absence of structural
heart disease.
used with caution in patients with congenital heart disease due
to the increased risk of ventricular proarrhythmia

Adverse Effects and Drug Interactions:

digoxin, warfarin, propranolol or metoprolol serum concentrations
increased with concomitant usage
Cimetidine can increases the propafenone serum concentration
ADR: dizziness, light-headedness, a metallic taste, nausea, and
vomiting.
Contraindications:
severe congestive heart failure, cardiogenic shock,
atrioventricular and intraventricular conduction
disorders, and sick sinus syndrome.
severe bradycardia, hypotension, obstructive
pulmonary disease, hepatic and renal failure.
 CLASS II

•Competitively inhibit β-adrenoceptors

•Propranolol and acebutolol cause electrophysiological
alterations in Purkinje fibers that resemble those produced by
class I antiarrhythmic drugs, referred as “membrane-stabilizing”
effects.
 Propranolol
Electrophysiological Actions:
has two separate and distinct effects.
1. β-adrenergic receptor blocking properties and the subsequent
removal of adrenergic influences on the heart.
2. direct myocardial effects (membrane stabilization) of
propranolol. account for its effectiveness against arrhythmias
SA node: Propranolol slows the spontaneous
firing rate of nodal cells by decreasing the slope
of
phase 4 depolarization
Atrium:
decreases action potential amplitude and excitability.
The serum concentrations at which the membrane stabilizing effects are similar
to those that produce β-blockade

AV node:
decrease in AV conduction velocity and an increase in the AV nodal refractory
period.

His-Purkinje system and ventricular muscle:

produces a depression of catecholamine-stimulated automaticity
At supra-normal concentrations, decreases Purkinje fiber membrane
responsiveness and reduces action potential amplitude

Electrocardiographic Changes:
The PR interval is prolonged with no change in the QRS interval.
The QT interval may be shortened
Clinical Uses:
•Useful for wide spectrum of arrhythmias
•Usually the initial therapy for SVT in all age groups
•Several forms of ventricular ectopy/ tachycardia including the
suppression of symptomatic PVCsa nd catecholamine dependent
Idiopathic VT.
•Propranolol is the drug of choice for treating patients with the
congenital long QT syndrome.
 Atenolol
Clinical Uses:
•All supraventricular tachycardias
•Control of ventricular ectopy
•Drug of choice for the initial therapy of SVT
 Nadolol

•long-acting nonselective β-adrenergic antagonist

•No membrane-stabilizing or intrinsic sympathomimetic activity

Clinical Uses:
treatment of various forms of supraventricular tachycardia and
long QT syndrome

Clinical Uses:
acute treatment of supraventricular and ventricular
tachyarrhythmias
acutely lowering blood pressure
 Esmolol
•short acting
•Intravenously administered β1 selective adrenoceptor blocking
agent
• It does not possess membrane-stabilizing activity or
sympathomimetic activity
 CLASS III

•Prolong the duration of the membrane action potential by

delaying repolarization without altering depolarization or the
resting membrane potential
•have a significant risk of pro-arrhythmia due to action potential
duration prolongation and the induction of torsades de pointes
 Amiodarone

•Iodine -containing benzofuran derivative

•Identified as a class III agent due to its predominant action
potential prolonging effects.
•Blocks sodium and calcium channels, as well as being a non-
competitive β-receptor blocker (class I, II, and IV actions).
•Effective agent for the treatment of most arrhythmias.
•drug be reserved for use in patients with life-threatening
arrhythmias.- due to toxicity
•prolongation of repolarization and refractoriness of cardiac
tissue
SA node:
Amiodarone and its metabolite desethylamiodarone inhibit
nodal function
His-Purkinje system and ventricular muscle:
Amiodarone and desethylamiodarone increase AV nodal
conduction time and refractory period.
The dominant effect on ventricular myocardium with chronic
treatment is a prolongation in the action potential duration and
increase in the refractory period with a modest decrease in
conduction velocity.
ECG: prolongation of the PR and QTc intervals
 PK
•Absorption is slow and the oral bioavialabiltiy is low (35%–65%)
drug is almost completely protein bound
•concentrated in the myocardium (10–50xserum concentration),
as well as in adiposetissue, the liver, and lungs (100–1000x
serum concentration).
•half-life ranges from 26–107 days with chronic administration.
•primary route of metabolism is hepatic with excretion via the
biliary tract.
•Therapeutic serum concentrations are 0.5– 2.5 μg/mL.
Clinical Uses:
•wide variety of cardiac rhythm disorders with minimal tendency for
induction of torsades de pointes
•wide range of arrhythmias, particularly in the post-operative period
including supraventricular tachycardia, atrial flutter,
• atrial fibrillation, intra-atrial reentrant tachycardia, junctional
ectocpic tachycardia, and ventricular tachycardia.
•The incidence of ventricular pro-arrhythmia is significantly less than
other class III agents.
•Its use, is limited by the multiple and severe non-cardiac side
•effects.
•Oral amiodarone is effective in most forms of supraventricular and
ventricular tachycardia
Because of its unknown effect on thyroid function and growth,
use of amiodarone for treating SVT is reserved for patients who
have failed several other medications and is time limited.

photosensitization and blue-gray Discoloration

Amiodarone inhibits the peripheral and intra-pituitary conversion
of thyroxine (T4) to triiodothyronine (T3) by inhibiting 5-
deiodination. The serum concentration of T4 is increased by a
decrease in its clearance, and increased synthesis due to a
reduced suppression of the pituitary thyrotropin, T3. The
concentration of T3 in the serum decreases and reverse T3
appears in increased amounts.
Adverse Effects:
chemical hepatitis,worsening sinus node dysfunction, thyroid
dysfunction (hypo or hyper), and pulmonary Fibrosis
the risk of torsades de pointes is relatively low.
Tremors of the hands and sleep disturbances, vivid dreams,
nightmares, insomnia. Ataxia, staggering, impaired ambulation,
Peripheral sensory and motor neuropathy or severe proximal
muscle weakness develops infrequently
Contraindications:
Sick sinus syndrome
crosses the placenta causing fetal bradycardia and thyroid
abnormalities
secreted in breast milk

Drug Interactions:
Amiodarone interferes with the metabolism of many drugs,
most notably warfarin and digoxin
 Sotalol
•Nonselective β-adrenoceptor blocking properties in addition to
class III actions via potassium channel blockade
•The β-blocking effects are most evident at lower doses
•Action potential prolonging effects predominating at higher doses.

SA node and atrium:

•Pacemaker activity in the SA node is decreased and increases the
refractory period of atrial muscle.

AV node:
•decreases conduction velocity and prolongs the effective refractory
period in the AV node.
His-Purkinje system and ventricular muscle:
•inhibition of the delayed rectifier potassium channel results in a
prolongation of the effective refractory period in His-Purkinje
tissue.
•prolongs repolarization and increases the ERP of ventricular
muscle.

ECG:decrease in heart rate and a prolongation of the PR and QTc

intervals
Pharmacokinetics:
Oral bioavailability of 50%
onset of action of 0.5 hours
plasma half-life of 4 hours
primary route of metabolism is hepatic with excretion primarily
in the urine (20% unchanged and 40% as metabolite)
Clinical Uses:
•Broad spectrum of antiarrhythmic effects in ventricular and
supraventricular arrhythmias.
•Use is limited by concerns for ventricular proarrhythmia.
•second-line medication for fetal arrhythmias.
Adverse Effects:
attributed to bothβ-adrenoceptor blockade
and pro-arrhythmia.
fatigue, dyspnea, chest pain, headache, nausea, and vomiting.

Contraindications:
severe heart failure or poor ventricular function.
patients with hypokalemia or prolonged QT intervals
 Dofetilide

“pure” class III drug.

It prolongs the cardiac action potential and the refractory period
by selectively inhibiting the rapid component of the delayed
rectifier potassium current (IKr).
 Ibutilide

structural analog of sotalol

produces cardiac electrophysiological effects similar to class III
agents
Due to its significant first pass metabolism, ibutilide is only
available as an intravenous preparation.
 CLASS IV
•Class IV drugs block the slow inward Ca2+ current (L-type calcium
channel).
•The most pronounced electrophysiological effects are exerted on
cardiac cells dependent on the Ca2+ channel for initiating the action
potential, such as those found in the SA and AV nodes.
•The administration of class IV drugs slows conduction velocity and
increases refractoriness in the AV node, thereby reducing the ability of
the AV node to conduct rapid impulses to the ventricle.
• This action may terminate supraventricular tachycardias and can
slow conduction during atrial flutter or fibrillation.
 Verapamil
SA node and atrium:
decreases the rate of SAnodal cells firing.
does not exert any significant electrophysiological effects on atrial
muscle.

AV node:
slows conduction through the AV node and prolongs the AV nodal
refractory period.

His-Purkinje system and ventricular muscle:

Verapamil has no effect on intraatrial and intraventricular conduction
Clinical Uses:
•Slowing the ventricular response to atrial tachyarrhythmias
such as atrial flutter and fibrillation.
•Ectopic atrial tachycardia and idiopathic LV-tachycardia
•Acute termination of supraventricular tachycardia that uses the
AV node as a critical component such as AVNRT and accessory
pathway mediated tachycardia.
 Diltiazem

The antiarrhythmic actions, electrophysiological effect and

clinical uses of diltiazem similar to those of verapamil
 MISCELLANEOUS
ANTIARRHYTHMIC AGENTS
 Digitalis Glycosides and
Vagomimetic Drugs
•Management of patients with supraventricular
arrhythmias
•slows conduction through the AV node making it
useful for use in reentrant arrhythmias that utilize the
AV node as one limb of the circuit.
 Adenosine
•used for the rapid termination of supraventricular arrhythmias
following rapid bolus dosing.
•Adenosine stimulation leads to a hyperpolarization of the resting
membrane potential, decrease in the slope of phase 4
depolarization, and shortening of the action potential duration.
• The effects on the AV node may result in complete conduction
block with termination of tachycardias utilizing the AV node as a
limb of a reentrant circuit.
•Adenosine does not affect the action potential of ventricular
myocytes because the adenosine-stimulated potassium channel
is absent in ventricular myocardium.
There is no effect on the QRS duration or QT interval.
Pharmacokinetics:
nearly instantaneous onset of action
rapidly metabolized by red blood cells
plasma half-life of less than 10 seconds
no orally available form.

Clinical Uses:
acute termination of supraventricular tachycardia that utilizes
the AV node
 ADR
flushing, chest pain, and dyspnea.
Adenosine may induce profound bronchospasm in
patients with known reactive airway disease. atrial
fibrillation
Contraindications:
asthmatic patients
Known hypersensitivity to adenosine

Drug Interactions:
Methylxanthines (such as theophylline) antagonize the effects of
adenosine via blockade of the adenosine receptors and
necessitate increased doses.
 Magnesium Sulfate

•Effective in terminating refractory ventricular tachyarrhythmias,

particularly polymorphic ventricular tachycardia.
•hypomagnesemia increases the likelihood of post-operative
junctional ectopic tachycardia
•Magnesium sulfate can be administered orally, intramuscularly,
or, preferably, intravenously, when a rapid response is intended.
•The loss of deep tendon reflexes is a sign of overdose.
 CARDIAC GLYCOSIDES
•They increase myocardial contractility and
output in a hypodynamic heart without a
proportionate increase in O2 consumption.
Thus, efficiency of failing heart is increased.
 PHARMACOLOGICAL ACTIONS
• Digoxin is described as prototype.
Heart
• direct effects on myocardial contractility and
electrophysiological properties
Force of contraction
Digitalis causes a dose dependent increase in force of
contraction of heart—a positive inotropic action
increased velocity of tension development and higher peak
tension can be generated
Systole is shortened, diastole is prolonged.
• The digitalized failing heart regains some of its
capacity to contract more forcefully when subjected
to increased resistance to ejection.
• There is more complete emptying of failing and
dilated ventricles—cardiac output is increased
• Tone
defined by the maximum length of the fibre at a
given filling pressure, or the resting tension in
the muscle fibre.
This is not affected by therapeutic doses of
digitalis
Rate
• Heart rate is decreased by digitalis.
• Bradycardia is more marked in CHF patients
• improved circulation (due to positive inotropic action)
restores the diminished vagal tone and abolishes sympathetic
over activity
Vagal tone is increased:
(a) Reflexly through ganglion and sensitization of baroreceptors.
(b) Direct stimulation of vagal centre.
(c) Sensitization of SA node to Ach

Extravagal:
A direct depressant action on SA and A-V nodes.
 Electrophysiological properties
• The resting membrane potential (RMP), is progressively
decreased (shifted towards isoelectric level) with increasing doses
• excitability is enhanced at low doses (due to reduction of gap
between RMP and threshold potential) but depressed at toxic
doses
• The rate of 0 phase depolarization is reduced.
• This action is most marked in A-V node and bundle of His.
• delayed after-depolarizations result
• The SA and A-V node automaticity is reduced at therapeutic
concentrations by vagal action which hyperpolarizes these cells
and reduces their phase-4 slope
Effective refractory period (ERP):
Excitability: Enhanced at low doses but depressed at high doses
Conduction: A-V conduction is demonstrably slowed by therapeutic
doses due to a reduction in the rate of 0 phase depolarization. At
high doses, intraventricular conduction in PFs is also depressed by
uncoupling of gap junctions.
ECG : Therapeutic doses of digitalis produce changes in the ECG. These
are accentuated at high doses—may also produce arrhythmias.
The changes are:
• Decreased amplitude or inversion of T wave.
• Increased P-R interval (slowing of A-V conduction), A-V block at toxic
doses.
• Shortening of Q-T interval (reflecting shortening of systole).
Mechanism of action
• Inhibition of Na+K+ ATPase is clearly involved in the toxic
actions of digitalis.
• At high doses, there is depletion of intracellular K+;
• toxicity is partially reversed by infusing K+.
 Blood vessels
Digitalis has mild direct vasoconstrictor action
Does not affect HF patients
No prominent effect on BP
No significant effect on coronary circulation

Kidney: Diuresis is seen promptly in CHF patients, secondary to

improvement in circulation and renal perfusion
 PHARMACOKINETICS
• Digitoxin is the most lipid soluble
• digoxin is relatively polar,
• Bioavailability of digoxin tablets from different manufacturers may
differ.
• Presence of food in stomach delays absorption of digoxin as well
as digitoxin
• Digitoxin is primarily metabolized in liver, partly to digoxin, and
undergoes some enterohepatic circulation.
• Digoxin is primarily excreted unchanged by the kidney
• rate of excretion is altered parallel to creatinine clearance.
• t½ is prolonged in elderly patients and in those with renal
insufficiency- dose has to be reduced
Cardiac glycosides are cumulative drugs
When maintenance doses are given from the beginning, steady
state levels and full therapeutic effect are attained after 4 ×
t½, i.e. 6–7 days for digoxin and 4 weeks for digitoxin
 ADVERSE EFFECTS
• Toxicity of digitalis is high
• margin of safety is low (therapeutic index 1.5–3)
• Higher cardiac mortality has been reported among patients
with
• steady-state plasma digoxin levels > 1.1 ng/ml during
maintenance therapy.
Extracardiac
Anorexia, nausea, vomiting and abdominal pain
Fatigue, no desire to walk or lift an arm, malaise, headache,
mental confusion, restlessness, hyperapnoea, disorientation,
psychosis and visual disturbances
Cardiac
Almost every type of arrhythmia can be
produced by digitalis:
pulsus bigeminus, nodal and ventricular extrasystoles,
ventricular tachycardia and terminally fibrillation.
Partial to complete A-V block may be the sole cardiac
toxicity or it may accompany other arrhythmias.
Severe bradycardia, atrial extrasystoles, AF or AFl
 PRECAUTIONS AND
CONTRAINDICATIONS
(a)Hypokalemia: enhances digitalis toxicity by increasing its binding to Na+K+
ATPase.
(b) Elderly, renal or severe hepatic disease: patients are more sensitive.
(c) Myocardial infarction: severe arrhythmias are more likely.
(d) Thyrotoxicosis: reduces responsiveness to digitalis, but these patients are more
prone to develop digitalis arrhythmias.
(e) Myxoedema: these patients eliminate digoxin more slowly; cumulative toxicity
can occur.
(f) Ventricular tachycardia: digitalis is contraindicated— may precipitate
ventricular fibrillation.
(g) Partial A-V block: may be converted to complete A-V block.
(h) Acute myocarditis: Diphtheria, acute rheumatic carditis, toxic carditis—
inotropic response is poor, more prone to arrhythmias
(i) Wolff-Parkinson-White syndrome: Digitalis is contraindicated
 INTERACTIONS
1. Diuretics
2. Calcium
3. Quinidine
4. Adrenergic drugs
5. metoclopramide (gastrointestinal hurrying) and sucralfate which
adsorbs digoxin. Antacids, neomycin, sulfasalazine also can
reduce digoxin absorption; stagger their administration.
Absorption is increased by atropinic drugs, including tricyclic
antidepressants, by delaying gastric emptying. Erythromycin,
omeprazole and tetracycline increase bioavailability of digoxin.
6. Propranolol, verapamil, diltiazem and disopyramide:
7. Phenobarbitone and other enzyme inducers
8. Succinylcholine
 USES
Congestive heart failure
 Cardiac arrhythmias
Atrial fibrillation (AF) Digitalis is the drug of choice for
controlling ventricular rate in AF, whether associated
with HF or Not
Digitalis reduces ventricular rate in AF by decreasing the
number of impulses that are able to pass down the A-V
node and bundle of Hish
Digitalis is given in AF, average ventricular rate decreases
in a dose-dependent manner and pulse deficit is
abolished because ventricle does not receive an impulse
very early in diastole before it has had time to fill
upreasonably.
• Atrial flutter (AFI)
• Paroxysmal supraventricular tachycardia
(PSVT)