Arrhythmias

Antiarrhythmic drugs
 Significance of cardiovascular diseases

Appoximately 2400 americanes die from cardiovascular diseases each

day

Over two million adults have sudden cardiac death each year

In the EU more than two million patients die each year

Vadnais D., Wenger N. 2010

 Causes of arrhythmias
► coronary heart disease – most common
► heart valve disorders
► drugs (stimulants)
► overactive or underactive thyroid gland
(hyperthyroidism, hypothyroidism)
► anatomic abnormalities of conduction
system

► electrolytes disturbances, acidosis

 Causes of arrhythmias (cont)

► exercise, stress, excessive alcohol

consumption, smoking can lead to fast heart
rate (tachycardia or tachyarrhythmias)

► pain, hunger, fatigue, digestive disorders -

diarrhea, vomiting - produce bradycardia or
bradyarhythmias through the stimulation of
vagus nerve

► sometimes no cause for an arrhythmia can

be identified
 Symptoms of arrhythmias

• palpitation

•weakness

• reduce capacity of exercise, shortness breath

• dizziness

• syncope

• some times there are not any symptoms

 Normal heart rate

60 between 90 (100)
 Cardiac conduction system

SAN Adrenergic division

1 АR
thyroid hormone
junctional area
bundle of His
Cholinergic
division left anterior fascicle
left posterior fascicle

right bundle left bundle

 Action Potential
Phase 1
Influx
Ca ++

Phase 2
Influx
Efflux
ERP
Na+
Phase 3
IKr
Phase 0
IKs Phase 4
 Principles underlying anti-arrhythmic
drug therapy

• Correct diagnosis

• Does the arrhythmia require treatment?

 Principles underlying anti-arrhythmic
drug therapy (cont)

• Correct diagnosis
• Does the arrhythmia require treatment?

are there any treatable does the benefit of treatment

outweigh
precipitating factors? the risk?
 Antiarrhythmic agents:
classification (Vaughan-Williams)
 Different antiarrhythmics
• Digoxin
• Adenosine (stimulates adenosine receptors A1
and A2, which blocks the entry of Calcium ions
and activastion of adenylatecyclase;
-stimulation of A1 receptors- development of
negative dromotropic action and slowing
down in the AV node)
Indications: paroxysmal supraventricular
tachycardia, including WPW
• magnesium salts
• potassium salts
 Classification of antiarrhythmic drugs
• Class I – inhibit the fast sodium channel

Ia – quinidine, procainamide, disopiramide

Ib – lidocaine, mexilitine, tocainide

Ic – propafenon, allapinine (moricizine)

Quinidine:
The oldest anti arrhythmic agents derived from the cinchona tree bark and has
anti malarial, anti pyretic and anti arrhythmic effects.
Elimination - hepatic and renal routes.
Side effects: GIT - nausea, abdominal pain and diarrhea; Allergic - rash, fever,
hemolytic anemia, thrombocytopenia and hepatitis. Cinchonism - quinidine’s
CNS side effects such as tinnitus, delirium, hearing and visual impairment. The
most serious side effect is polymorphic ventricular tachycardia / torsade de
pointe.

Procainamide
Excretion - by the kidneys, its main metabolites, N-acetyl procainamide
(NAPA) is a pure potassium channel blocker and is exclusively renally
excreted.
Procainamide is effective in treating supraventricular and ventricular
arrhythmias.
Side effects: agranulocytosis, lupus like syndrome with arthralgias, myalgias,
pleuritis, pericarditis (polyserositis) and rash may occur.
Lidocaine, phenitoine (difenine) and mexiletine are class IB anti arrhythmic agents
used only the management of ventricular tachyarrhythmias.

Lidocaine can only be given intravenously and is metabolized in the liver. Dose
should be adjusted in patients with liver disease and heart failure.
Lidocaine toxicity manifests itself with CNS side effects; parasthesias, confusion and
seizures.

Mexiletine is used orally, its side effects are CNS; tremors, confusion, blurred vision
and gastrointestional; nausea and vomiting.
Allapinine (moracizine) and propafenone are class IC anti arrhythmic agents.
They are used to treat ventricular and supraventricular tachyarrhythmias.
Contraindications: structural heart disease due to the risk of precipitating life-
threatening ventricular arrhythmias (see CAST study above).
These drugs can depress systolic function. They can suppress the sinus node
in patients with sick sinus syndrome and impair AV and infra nodal conduction
in patients with conduction disease. Propafenone has beta adrenergic receptor
blocking effect.
 Classification of antiarrhythmic drugs
• Class II – ß-blockers (antiadrenergic actions)
• Propranolol
• Atenolol
• Metoprolol (BETALOC 25, 50, 100 mg tab, 5 mg-10/ml inj. Daily,
LOPRESOR, METOLAR 50, 100 mg tab.)
• Esmolol-50-200 mcgms/kg/minute i/v
• Bisoprolol(CONCOR, CORBIS 5 mg tab; ½ to 2 tab OD.)
• Nadolol
• Carvedilol
 Classification of antiarrhythmic drugs (cont)

• Class III – prolong refractoriness by potassium block

amiodarone, sotalol, bretilium, dofetilide, ibutilide,
dronedarone

• Class IV – ions calcium block

verapamil, diltiazem
 Class III
Sotalol is a non specific beta adrenergic receptor blocker with potassium channel
blocking properties used in managing ventricular arrhythmias and atrial fibrillation.
Excretion – by kidneys. Side effects: torsade de pointe.
Due to its beta adrenoreceptor blocking effect, patients with bronchospastic disease
may experience an exacerbation of their pulmonary disease.
Ibutilide is a short acting intravenous potassium channel blocker used only for the
acute termination of atrial fibrillation or flutter.
It can cause sustained ventricular arrhythmias.
Dofetilide is a potassium channel blocker excreted by the kidneys.
Dosage is determined by creatinine clearance and adjusted according to changes in
the corrected QT (QTc) interval.
Amiodarone -Although classified as a class III agent, it displays use dependent
sodium channel blockade, noncompetitive alpha and beta adrenoreceptor blockade
and calcium channel blockade.
It reduces the conversion of T4 to T3 and increases rT3. Amiodarone is also a
vasodilator.
Indications: atrial fibrillation and recurrent ventricular arrhythmias/Use: intravenously
and orally.
Amiodarone has a very long half-life (40-50 days). In order to achieve rapid
therapeutic levels, the drug should be loaded.It is hepatically excreted with no renal
excretion. Amiodarone toxicity is influenced by the dosage employed and the
duration of its use.
 Mechanism of action of amiodarone

Blockade of Na-channels (resemble effect of drugs 1 class)

Blockade of α & β adrenoceptors (II class)

Elongation repolarization (III класс)

Blockade of Са- channels (IV class)

Results -  action potential & effective refractory period

 Pharmacokinetics of amiodarone

Вioavailability (after take it) – ≈ 50%

Tmax - 3-7 час.

Onset of action – in a few days (2-3), max 2-3 weeks

Biliary excretion (dose still the same in chronic renal insufficient)

Т1/2 - 26-107 days (at the average 53 days)

 Amiodarone
Doses
Onset of treatment – oral loading dose
range 600-800 mg/day (in divided daily doses) in a first
week, then
200-400 mg/day (given once daily) in a next week
Maintenance therapy
200 mg once a day
Intravenously 5 mg/kg during 20 мin.
 Analog amiodarone
Dronedarone
a last new analog of amiodarone, which is
non-iodinated substance

Unlike amiodarone, dronedarone has very

minimal effect on thyroid function

Dronedarone has a similar pulmonary toxicityiv

10-30 mg/kg or oral 600-800 mg/d
 Side effects of amiodarone (cont)

Vision organs
Retrobulbar neuritis, scotoma(a partial loss of vision), deposits in cornea
Skin
photosensibilization, rash, dermatitis
Endocrinological SE
Thyrotoxicosis, hypothyroidism ,
Proarrhythmic effects
 Side effects of amiodarone (cont)

• Pulmonary toxicity:

Interstitial pneumonitis

Alveolar pneumonitis
 Side effects AD
Procainamide – SLE, GI(nausea, anorexia), blood pressure fall,
Disopyramide aggravation of underlying heart failure, conduc
tion disturbances, ventricular arrhythmias,
agranulocytosis, anticholinergic effects,
hypoglycemia, hepatic cholestasis
Lidocaine - CNS (confusion, tremor, ataxia, seizures), conduction disturban-
Mexiletine ces, ventricular arrhythmias, thrombocytopenia
Tocainide

Moricizine - blurred vision, dizziness, headache, GI, bronch-

Propafenone ospasm, ventricular arrhythmias, conduction
disturbances
 Side effects AD (cont)
ß-blockers bradycardia, bronchospasm, disturbance of
AV-conduction

Amiodarone CNS, corneal microdeposits, neuropathy,

Dofetilide GI, pulmonary fibrosis, hepatitis, disturbances
Ibutilide of thyroid function (hypothyroidism, hyperthyroidism), photosen-
Sotalol sitivity, agranulocytosis, bronchospasm,
Dronedarone ventricular arrhythmias or conduction disturban
ces

Verapamil - conduction disturbances

Diltiazem
Side effects AD (cont)

Proarrhythmic effect

Torsades de pointes (TdP)

TdP - High Risk Drugs (>
1%)
Therapeutic Effect Is Linked to IKr Block
 Quinidine
 Disopyramide
 Sotalol
 Ibutilide
 Dofetilide
 Accessory A-V connection (WPW-syndrome) Wolf-Parkinson-
White tachycardia

orthodromic (anterograde signal passes through A-B node and then retrograde
through an additional beam returns, which forms the excitation circulation)
antidromic (anterograde signal passes through an additional beam and then
retrograde through A-B node returns, which forms the excitation
circulation)
ECG - QT Interval
Torsades de Pointes
 Drugs Which Prolong the QTc
Anticonvulsants Fosphenytoin; Felbamate
Antihistamines Azelastine; Clemastine
Anti-Infectives Amantadine; Clarithromycin; Chloroquine; Foscarnet;
Erythromycin; Halofantrine; Mefloquine; Moxifloxacin;
Pentamidine; Sparfloxacin; Quinine; Trimethoprim-
Sulfamethoxazole, Ketoconazole
Antineoplastics Tamoxifen
Cardiovascular: Antiarrhythmics Amiodarone; Bretylium; Disopyramide; Flecainide;
Ibutilide; Procainamide; Quinidine; Sotalol; Dofetilide
Calcium Channel Blockers Bepridil; Israpidine; Nicardipine
Diuretics Indapamide; Moexipril/HCTZ
Hormones Octreotide; Vasopressin
Immunosuppressives Tacrolimus
Migraine: Serotonin Receptor Agonists Zolmitriptan; Naratriptan; Sumatriptan
Muscle Relaxant Tizanidine
Narcotic Detoxification Levomethadyl
Psychotherapeutics: Antidepressants Amitriptyline; Desipramine; Fluoxetine; Imipramine; Venlafaxine
Antipsychotic Chlorpromazine; Haloperidol; Pimozide; Quetiapine;
Risperidone; Thioridazine
Antianxiety Doxepin
Antimanic Lithium
Respiratory: Sympathomimetics Salmeterol
Sedative/Hypnotics Chloral hydrate

http://www.dml.georgetown.edu/depts/pharmacology/torsades.html
http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/publicat/adrv8n1_e.html
Mechanisms Of Drug - Induced
QT Prolongation and Tdp

• Block of repolarizing K+ currents

• Stimulation of ICa-l
• Stimulation of INa
Mechanism of Torsades de Pointes

 Early afterdepolarizations
 Transmural reentry
Automated QT and QTc
Analysis
 Reliable with normal T waves at
physiologic heart rates
 Unreliable:
 High heart rates
 Abnormal T waves
 Prominent U waves

 T-U wave complex morphology

 TdP - Low Risk Drugs (<
0.1%)
Therapeutic Effect Is Independent of IKr Block

 Antihistamines
 Antibiotics
 Antiviral agents
 Psychotropics
 Many others
Drug-Induced Torsades de
Pointes
 Primary: Drug effect (IKr block)
 Secondary: Effect Amplifiers
 Bradycardia
 Hypokalemia
 Heart disease (LVH or CHF)
 Atrial fibrillation
 Female gender
 Undetected HERG mutation
 High doses
 Metabolic inhibitors (PK)
 Concomitant IKr blockers (PD)
Drug-Induced QT Interval Prolongation and Torsades de
Pointes

CYP450 3A4 Inhibitors+antiarrhythmic agents –III class

• Amiodarone
• Cimetidine
• Fluoxetine
• Grapefruit juice
• Protease inhibitors
• Ketoconazole; itraconazole
• Macrolide antibiotics (not Azithromycin)
• Nefazadone
Drug Induced Torsades de Pointes
Drug EP Effects Metabolic Liability

Terfenadine IKr blocker 3A4 substrate

Cisapride IKr blocker 3A4 substrate
Mibefradil IKr blocker 3A4 inhibitor
Erythromycin IKr blocker 3A4 inhibitor
Astemizole IKr blocker 3A4 substrate
Dofetilide IKr blocker Renal excretion
Sotalol IKr blocker Renal excretion
 Drugs Withdrawn for TdP

Drug Class Date Withdrawn

Terfenadine Antihistamine Feb 1998
Sertindole Antipsychotic Dec 1998
Astemizole Antihistamine Jun 1999
Grepafloxacin Antibiotic Nov 1999
Cisapride GI Prokinetic July 2000