Cardio-vascular Pharmacology By

Professor Doctor: Abd Al Rahman Abd Al Fattah

YassinProfessor and head of clinical pharmacology

departmentMansura university

ANTIARRHYTHMIC DRUGS

CARDIAC ARRHYTHMIAS• It is an abnormality of rate, site of origin of

cardiac impulse or disturbance in conduction that causes alteration in normal sequence of activation of the atria and ventricles.

• All arrhythmia Result From• Disturbance of impulse formation• Abnormalities of impulse conduction.• Both. • Disturbance of Impulse Formation • This occurs due to either enhancement or failure

of normal automaticity.

Arrhythmias can be precipitated by: • hypoxia,acidosis,alkalosis,electrolyt

e disturbances,excess catecholamines, drug toxicity (e.g. quinidine sotalol, phenothia-zine and cisapride), overstretching of cardiac fibers.

Arrhythmias may be one of the following:1. Sinus tachycardia. 2. Sinus bradycardia 3. Extra systoles4. Atrial flutter 5. Atrial fibrillation6. Paroxysmal atrial tachycardia7. Paroxysmal ventricular tachycardia8. Ventricular fibrillation

9. Heart block• It may result from congenital, ishaemic heart disease, overdose of

digitalis or potassium intoxication. It is classified into 3 grades.

8. Bundle branch block• Block of conduction in one of the two main branches of bundle of

His.N.B.

Wolf-Parkinson-White Syndrome (WPW):• It is due to an accessory atrioventricular pathway which conduct

more rapidly than normal pathway and one ventricle is excited early.

Rrespiratory sinus arrhythmias: heart rate increase during inspiration and decrease during expiration.

ANTIARRHYTHMIC DRUGS• Non-pharmacological techniques for

arrhythmia treatment are preferred because:• Arrhythmogenic effect of the drugs

used in treatment of arrhythmias.• Efficacy of these methods.

Non Pharmacological techniques

• Ablation technique..

• Implantable cardiovector defibrillator .

• Artificial pacemaker.

Mechanistic Classifications • CLASS I (SODIUM CHANNEL BLOCKERS)

• Ia: .e.g. Quinidine, disopyramide, procainamide.

• Ib: . .e.g. Lidocaine, mexilitene, aprinidine, tocainide.

• Ic: e.g. flecainide, lorcainide or encainide.

CLASS II (BETA-BLOCKERS)•They include esmolol, metoprolol and propranolol.

•CLASS III (POTASSIUM CHANNEL BLOCKERS)•.e.g.: Amiodarone, bretylium, ibulilide and sotalol.

•CLASS IV

• Calcium channel blockers e.g. verapamil, diltiazem

•Potassium channel openers e.g. adenosine, cromakalim,

pinacidil.

Therapeutic Classification of Antiarrhythmic Drugs

• Supraventricular arrhythmias: adenosine, verapamil, digoxin or beta-blockers • Ventricular arrhythmias: Lidocaine,

mexiletine, disopyramide or sotalol.• Supraventicular and ventricular

arrhytmias: Amiodarone, quinidine or beta adrenoceptor blockers.

CLASS Ia ANTIARRHYTHMICSQUINIDINE

• It is an alkaloid of Cinchona bark. It is dextroisomer of quinine.

Pharmacokinetics• Absorption from the gut is about 70%.• ..• The half-life is 7-9 hours.• Protein binding 80-90%• Metabolized in the liver.• Plasma levels for antiarrhythmic effects are 2-5g/ml.

Pharmacodynamics• Its antiarrhythmic action: block sodium channels.• Quinidine has atropine like action. and alpha

adrenoceptor blocking properties. .

Pharmacological Effects Effects on the cardiovascular system Cardiac effects•Negative inotropic effect.•Depression of excitability.•ENHANCE conductivity in the A-V node and bundle of His . It suppresses enhanced automaticity .•Effect on the E.C.G:•Prolongation of Q-T interval .•Prolongation of P-R interval•Decrease in amplitude or inversion of T wave•Widening of Q.R.S. complex

.

Effect on blood vessels and BP:

• vasodilatation and hypotension with large dose. Autonomic effects• Quinidine has atropine like effect and alpha

adrenocepetor blocking properties.Other pharmacological actions• It possesses antimalarial, antipyretic, analgesic,

oxytocic and skeletal muscle relaxant, but it is not used clinically for these purposes.

Therapeutic Indications• Atrial fibrillation (of less than 6 months duration).

Patient should be digitalized before quinidine to prevent the possible occurrence of "Paradoxical tachycardia".

• Atrial flutter: It is less active than in atrial fibrillation and can be used when digitalis fails.

• Paroxysmal atrial tachycardia.• Extrasystoles. Atrial and ventricular. • Ventricular tachycardias.• Maintenance of sinus rhythm after successful direct

current cardioversion.

Side Effects and Toxicity• Idiosyncrasy.• Cinchonism.

• Embolism.• Paradoxical tachycardia. • Quinidine syncope. • Hypotension: particularly if given intravenously.

Contraindications • Complete A.V block with an A.V. pacemaker

or idioventricular rhythm.• Old standing atrial fibrillation.• Prolongation of Q.T. interval. • Congestive heart failure.• Hypotension.• Hypersensitivity.• Myasthenia gravis.

Preparations and Dosage• Oral: Quinidine sulphate, available as 0.2 gm tab. or

capsules.• A test dose is given at first .• The usual schedule is as follows: 0.2 gm, 2 hourly

for 5 doses which may be increased to 0.4 gm, on the next day ..).

• Parenteral: Quinidine gluconate administered i.m, or i.v. in emergencies.

PROCAINAMIDE

Pharmacological Effects• Cardiac effects: Similar to quinidine•Autonomic effects: It has weaker anticholinergic effects.it has a ganglion blocking effect. Therapeutic Uses Ventricular arrhythmias Supraventricular arrhythmias.

CLASS Ib ANTIARRHYTHMICS LIDOCAINE• Its oral administration results in a very low plasma

concentration due to its massive first-pass metabolism • Pharmacological Effects.• It decrease pacemaker activity of Purkinjie fibers.• It has no effects on SAN• Lidocaine decreases membrane excitability of Purkinjie

fibers.

.

Therapeutic Uses• In most ventricular arrhythmias .• In digitalis induced arrhythmias

Adverse Effects• It is the least cardio toxic of antiarrhythmic but it may

worsen impaired conduction• Perioral paresthesia, tremors, dizziness, and slurred

speech

Dosage: It is given in loading dose of 1-2 mg /kg as an I.V bolus injection followed by a maintenance infusion of 2-4 mg/min. A constant infusion would take 5-9 hours to achieve therapeutic level.

PHENYTOIN (DIPHENYLHYDANTOIN, DPH)• It is effective in treating epileptic seizures as

well as ventricular arrhythmias.• Pharmacokinetics• It is slowly absorbed after oral

administration • It is inactivated by microsomal enzymes in

the liver.• About 90 % is bound to plasma protein

PHARMACOLOGICAL EFFECTS

• Effect on the heart: similar to lidocaine

• Effect on the autonomic nervous system: It exerts a depressant

effect on sympathetic centers in the CNS .

• THERAPEUTIC USES

• Digitalis induced cardiac arrhythmias

• Ventricular arrhythmias .

• Antiepileptic drug.

• ADVERSE EFFECTS • CNS side effects: nystagmus, vertigo, dysarthria

and confusion.• Hepatotoxicity, lymphadenopathy, gingival

hyperplasia, hirsutism, megaloblastic anaemia, hypotension.

• DOSAGE: IVI 50-100 MG/5 MINUTES THEN MAINTAIN ON 400 MG/DAY ORALLY AFTER CONTROL OF ARRHYTHMIAS.

CLASS Ic ANTIARRHYTHMICSFLECAINDIE and ENCAINIDE

PROPAFENONE It is class Ic antiarrhythmic drug with some beta-

blocking, class III, and class IV activities.Uses: ventricular, supraventricular arrhythmia and WPW syndrome.Side effects: A-V block, visual disturbance, metallic taste, and constipation.

•

CLASS IIBETA-ADRENOCEPTOR BLOCKERS

• .

• The antidysrythmic effects of these drugs is probably due to beta receptor

blockade .Beta-blockers slow automaticity in sinus and ectopic pacemakers.

The principal effect is the depression of phase –4 depolarization.

• Propranolol has class I & IV properties, sotalol has class III properties.

• Therapeutic Uses : Supraventricular arrhythmias.

• In digitalis - induced ventricular arrhythmias.

• It is the drug of choice for chest pain and arrhythmias of mitral valve prolapse.

•

CLASS III AMIODARONE

•It is well absorbed orally. Extensively bound to tissues and slowly metabolized by the liver. Pharmacological Effects

•It produces prolongation of action potential duration through blockade of potassium channel.•Blocking Na+ channels (Class I activity).•Blocking and adrenergic receptors (Class II activity).•Weak Ca++ channel blockers (Class IV activity).•Amiodarone is a potent smooth muscle relaxant, producing marked coronary and peripheral vasodilatation.

Therapeutic Uses• Supraventricular and ventricular arrhythmias.• Arrythmias associated with WPW syndrome.• Control of recurrent ventricular tachycardia or

fibrillation in patients resistant to other aniarrhythmic drugs.

Adverse Effects• Corneal microdeposists, alteration of thyroid function,

photosensitivity, pulmonary infiltration, myopathy, peripheral neuropathy, hepatotoxicity, sleeplessness, A-V block and sinus bradycardia.

Dosage: It is given once per day. A loading dose of 0.8 - 1.2 gm/day is given for 2-4 weeks and maintain on 0.2 - 0.8 gm/day.

CLASS IVCALCIUM CHANNEL BLOCKERS

• The pharmacology of this class of drugs was discussed.

• Calcium channel blockers that are used are verapamil and diltiazem.

• VERAPAMILIS EFFECTIVE PREVENTING SUPRAVENTRICULAR TACHYCARDIA AND IN REDUCING THE VENTRICULAR RATE IN ATRIAL FIBRILLATION AND FLUTTER.

• MECHANISM OF ACTION: It acts by delaying impulse transmission through the A.V node as a result of blocking calcium channels.

OTHER ANTIARRHYTHMICS

• ADENOSINE • It is a potassium channel opener.• It is used in AV tachycardia in WPW syndrome.

Adenosine also has been used to produce controlled hypotension during some surgical procedures and in the diagnoses of coronary artery disease.

DIGOXIN• .. Digoxin is used to control the ventricular response rate in atrial fibrillation and flutter.

MAGNESIUM SULFATE• Magnesium sulfate is administered intravenously to suppress drug-

induced torsade de pointes, to treat digitalis-induced ventricular arrhythmias, and to treat supraventricular arrhythmias associated with magnesium deficiency.

• ELECTRIC SHOCK THERAPY• Direct current electric shock applied externally can be used to

convert cardiac arrhythmias to normal sinus rhythm.it has been successfully applied to arrest atrial flutter and fibrillation, supraventricular and ventricular tachycardia and ventricular fibrillation. It is a method of choice in the emergency treatment of these arrhythemias. It is dangerous in presence of digitalis toxicity.

CLINICAL APPLICATIONS OF ANTIARRHYTHMIC DRUGS

Atrial Fibrillation• Emergency Treatment• Digitalis IV is the drug of choice.• Cardioversion can be used .

• Non-emergency Treatment• Digitalis is given orally.• Quinidine may be used to convert atrial fibrillation

to sinus rhythm

Atrial Flutter• Emergency Treatment • Cardioversion or • I.V. digitalis • Non-Emergency Treatment• Digitalis is given orally .

Wolf-Parkinson-White (WPW) Syndrome• Amiodarone • Sotalol or propranolol plus procainamide or quinidine • Cardioversion should be used if the patient shows signs

of CHF or angina.

Junctional Tachycardias• Vagotonic maneuvers ..• I.V. verapamil, esmolol and adenosine are the drugs of

choice and the response is usually diagnostic.• Class Ia or Ic antiarrthythimcs are also useful.• Avoid recurrence by the use of class Ia, III or IV

antiarrhythmics.

Ventricular Tachycardias• Emergency Treatment• Lidocaine is the first choice if the patient is haemodynamically

stable.• Recently I.V. amiodarone has been used to suppress ventricular

tachycardias.• Cardioversion is used if ventricular tachycardia persists after

lidocaine provided it is not due to digitalis toxicity and if the patient is unstable.

• Prophylaxis• I.V. drips lidocaine should be continued for at least 48-72

after the return of sinus rhythm.• Oral quinidine should be continued for at least 3 months

especially if there is acute myocardial infarction.

Torsade de pointes • Patients with this arrhythmia may be treated by intravenous

administration of magnesium sulfate, cardiac pacing.

Ventricular fibrillation• Lidocaine, procainamide, or bretylium has been used as an adjunct treatment

and is usually administered before and between attempts at electrical defibrillation. Recently, amiodarone has also been used for this purpose. Long-term preventive therapy may include an implantable cardioverter–defibrillator.

Bradyarrhythmias and Heart Block• Cardiac pacemaker ..• Atropine I.V. .• Hydrocortisone I.V. in acute cases of heart block e.g. following infarction

hydrocortisone suppresses inflammatory reaction in the conducing tissue.