CARDIAC ANTIDYSRHYMIC DRUGS

Definition

I: Any disorder of Cardiac rhythm is called DYSRHYMIA

II CAUSES

d) Disorder of impulse generation

e) Disorder of impulse Conduction

f) a+ b (above)

III Factors Predisposing to Cardiac dysrrhythmias

May Include: Local ischaemia to the heart + (MI) Digitalis toxicity Catecholamine's Local ionic changes ( Ca ++ and K

+)

These factors may increase pacemaker activity in ectopic foci generating enhanced automaticity and dysrrhythmias

IV) Ionic basis of a normal Cardiac action potential

A normal cardiac action potential can be illustrated in figure 1 below

Fig.1

O 1 2 o -90 3

4 MV (a) Cardiac muscle cell action potential

Explanations

Phase O = Is a rapid depolarization and is primarily due to influx of Na + ions

Phase 1 = Is a rapid repolarization and appears to be secondary to outward K+ (exflux) plus inactivation of Na+ influx

Phase 2 = Is the plateau phase and is primarily due to Ca ++ influx

Phase 3= Rapid repolarization due to K + efflux

Phase 4 = Resting membrane potential

TYPES OF DYSRHYTHMIAS.

C) Disorders of impulse generation. Atrial flutter characterized by a regular and

very fast atrial rate ( 150-350/ min) Atrial fibrillation

The atrial action potential is in the range of 200-600/min. The abnormality is due to the presence of multiple atrial ectopic foci.

Tachycardia

Supraventricular paroxysmal tachycardia Ventricular fibrillation Ventricular paroxysmal tachycardia

B) Disorders of impulse Conduction Heart block. Common sites of heart block

occur in the AV node and the bundle of His. There are different degrees of Heart + block.

Re-entry dysrrhythmias These could occur anywhere in the cardiac muscle especially

where they are damaged.

Right His bundle Branch

(a)

i

b)

c)

Re- establishment of a re-entry Cardiac dysrhythmia

a = normal conduction

b = Uni-directional block in bundle of His branch

c= Retrograde transmission through ® His

Antiarrhythmic Drugs Antiarrhythmic drugs act by blocking myocardial Na+, K+

or Ca++ channels. Some have additional or even primary autonomic effects. Classification of antiarrythmic drugs has been unsatisfactory because many have more than one action.

Class 1: Membrane stabilizing agents i.e. Na+ channel blockers

Examples of drugs that (a) moderately decrease O-phase, Quinidine, Procainamide, Dosopyramide, Moricizine

(b). Drugs that little decrease O-Phase, Lidocaine, Tocainide, Phenytoin, Mexiletine

(c). Drugs that cause marked decrease of O-phase, Flecainide, Encainide, Propafenone

Class 11: Antiadrenergic agents or Beta blockers e.g. Propranolol, Esmolol, Sotalol

Class 111: Agents widening AP (i.e. prolonging repolarization (e.g. Amiodarone, Bretylium

Class IV: Calcium channel blockers e.g. Verapamil, Diltiazem

Note that class one agents also have class 111 properties and Propranolol has class 1 actions as well, sotalol and Bretylium have both class 11 and 111 actions

Others include: Adenosines, digitalis, sympathomimetics such as Isoprenaline, and anticholinergics like Atropine and Quinidine.

Note: Most antiarrthymics can themselves precipitate serious arrthymias. Hence are known as to have Arrthymogenic potential of antiarrthymics.

Class 1: The primary actions of drugs in this class is to limit the conductance of Na+ and K+ across cell membrane – a local anesthetic action.

They interfere with depolarization and decrease responsiveness to excitation. They also reduce the rate of phase 4 depolarization in automatic cells

MOA OF QUINIDINE: It is an alkaloid from Cinchona bark and a

dextro-isomer of quinine. Blocks myocardial Na+ channels leading to

reduction in myocardial automaticity It also decreases availability Na+, Ca++ and

K+ as well delays their reactivation BP: it has some alpha adrenergic blocking

properties. At high doses it dilates blood vessels leading

to fall of BP Skeletal muscles: Like quinine it decreases

contractility of skeletal muscles by direct action

GIT: Quinidine is bitter and irritant, can lead to nausea, vomiting and diarrhoea

CNS: Neurological effects may be seen at high doses

Uterus: Increases uterine contractions, but not a useful oxytocic

Antimalarial action: Poorer than quinine Kinetics: More than 75% of the drug (quinidine

sulfate) is taken and absorbed orally, peak concs occurring at 1-2 hrs, 80-90% bound to plasma proteins, metabolized in the liver by hydroxylation and eliminated via the kidneys in urine in 24 hrs and a half life of 6 hrs

Routes of administration: orally, or by slow I.V but not IM because it causes pain and local necrosis

S/E: Incidence of side effects with quinidine are high and the drug is not tolerated by many patients, risk of sudden death due to cardiac arrest, GIT intolerance is most common, hypersensitivity reactions (thrombocytopenia) though rare, can precipitate failure in a dose related manner, fall in BP and syncope occur after I.V use. Higher dose can precipitate arrthymias by prolonging the QRS and Q-T intervals, can cause paradoxical tachycardia and reduces atrial rate because quinidine is a cardiac depressant

C.Is of Quinidine Intolerance or idiosyncrasy especially

thrombocytopenia Heart Block, may enhance degree of block or

suppress ventricular pacemaker in complete heart block

CHF and hypotensive states may be worsened History of embolism as it may led to throwing out

more emboli from fibrillating atria Uses. Quinidine is effective in large number of atrial

and ventricular arrhythmias, but not preferred drug for treatment of acute arrhythmias but now is used to maintain sinus rhythm after atrial fibrillation

Interactions with Quinidine Increases plasma concs of Digoxin by displacing it

from tissue binding sites and decreasing its renal and biliary clearance, thus precipitating digitalis toxicity

Diuretics by inducing hypokalemia Vasodilators given to pts receiving quinidine

produces synergistic fall in BP leading to syncope occurring on standing

Enzyme inducers (phenorbabitone, phenytoin) reduce duration of action of quinidine, whereas, verapamil and cemetidine can increase quinidine duration of action and palsma levels

Inhibits CYP2D6, thereby reducing conversion of codeine to morphine

Produces synergistic cardiac depression with K+ salts and Beta Blockers

Procainamide, is an amide derivative of the local anesthetic procaine, was found to have arrhythmic activity but not useful clinically due to rapid hydrolysis and marked CNS effects, but orally active

Cardiac electrophysiological actions are similar to those of quinidine but differs in the followings

3. Procainamide is less potent

4. Causes less marked depression of contractility and A-V conduction

5. Antivagal actions are minimal

6. Is not an alpha blocker and causes less Fall in BP at high doses, a fall in BP is normally due to ganlionic blockade

Kinetics of Procainamide: Oral bioavailability is about 75%, peak plasma

concs occurs within 1 hr, protein binding is minimal but distribution is wide.

Drugs is metabolized in the liver by acetylation to N-acetyl-procainamide (NAPA) which has no Na+ channel bloking property but blocks K+ channels and prolongs repolarization

SE of Procainamide: GIT intolerance is better than quinidine, but nausea

and vomiting do occur, CNS effects weakness, mental confusion and hallucinations at higher doses, flushing and hypotension are seen on rapid IV injection, cardiac toxicity and paradoxical tachycardia are similar to quinidine, hypersensitivity reactions like fever, rashes, angioedema are common and rarely aplastic anaemia and agranulocytosis

Interactions with Procainamide: Reduces the antimicrobial effects of

sulfonamides probably by generating PABA

Uses: Is used as an alternative to quinidine as they

have similar spectrum of efficacy Some pts not responding to one may respond

to the other Procainamide is not preferred for prolonged

use orally because of frequent dosing and the high incidence of lupus.

For IV use it is safer than quinidine and has rapid action

Disopyramide: Is a quinidine like drug which has prominent cardiac

depressant and anticholinergic actions but lacking alpha adrenergic blocking properties

Has no effect on sinus rate because of opposing direct depressant and antivagal actions

Causes less marked prolongation of P-R intervals and QRS broadening

Kinetics. Orally taken, and bioavailability 80%, metabolized in the liver by deakylation, raely given slowly by IV route, half excreted unchanged in urine, plasma half life is 6-8 hrs. The half life is increased in pts with MI and renal insufficiency

S/E of Disopyramide: Better tolerated than quinidine, less GIT effects, has

anticholinergic effects which are very common such as dry mouth, constipation, urinary retention esp in elderly and blurred vision

Can cause greater depression of cardiac contractility, hypotension in pts with damaged hearts because it increases peripheral resistance and may decrease cardiac output

C.Is: include sick sinus, CF and prostate hypertrophy

Indications; include prevention of reccurrences of ventricular arrhythmias and as maintenance therapy for cardioversion of atrial fibrillations.

Lidocaine (Lignocaine), is the commonest used Las agents. It is also a popular antiarrhythmic in intensive care units

The drug supresses automaticity in ectopic foci i.e. at stage or phase 4 depolarization

Is a blocker of inactivated Na+ channels, but does not affect normal ventricular and conducting fibres, however, it affects or depresses significantly depolarized or damaged

It has minimal effects on normal ECG, QRS broadening does not occur, may decrease the QT intervals

Causes less depression of cardiac contractility or arterial BP

Kinetics: the drug is absorbed orally but because of high first pass metabolism in liver, adequate and consistent blood levels are not achieved as it gets inactivated by this route

It is 75% plasma protein bound and actions of a bolus dose by IV lasts only 10-20 min only because of rapid redistribution.

It is hydrolysed, deethylated and conjugated in the liver and excreted in urine

It had an early t half of 8min and later elimination phase of 2 hrs. The t half is prolonged in CHF because of a decrease in volume of distribution and hepatic blood flow

Routes mainly IV and orally S/E; are neurological dose related such as

drowsiness, nausea, paresthesias, blurred vision, disorientation, twitches and fits.

Excessive doses causes cardiac depression and hypotension

Mexiletine: is a Local anaesthetic agent and an active antiarrhythmic drug by oral route.

It is chemically and pharmacologically similar to lidocaine Kinetics, the drug is almost completely absorbed orally, 90%

metabolized in the liver and excreted in urine Plasma half life is 9-12 hrs. Morphine has been shown to reduce its oral absorption Phenytoin and rifampicin induces its metabolism S/E are relatively high e.g. bradycardia, hypotension, and

accentuation of AV block, neurological such as tremor, nausea, vomiting, dizzness, confusion, blurred vision and ataxia can occur

Uses: Parenteral route is useful in post infarction ventricular arrhythmias as an alternative to Lidocaine resistant cases

Another drug similar to lidocaine; is Tocainide. Is effective in ventricular arrhythmias, but rarely used because of risk of agranulocytosis, thrombocytopenia, and pulmonary fibrosis

Propranolol: is one of the drugs which are considered to suppress adrenergically mediated ectopic activity.

Thus, some beta blockers like propranolol have quinidine like direct membrane stabilizing actions at high doses

However, in the clinically used dose range these drugs have antiarrhythmic actions primarily because of cardiac adrenergic blocakde

Propranolol decreases the slope of phase 4 depolarization and automaticity of the SA node

Uses: useful in treating sinus tachycardia, atrial fibrillation provoked by emotions, or exercise

Given by IV route, rarely abolishes AF, highly effective in sympathetically mediated arrhythmias seen in phaechromocytoma and during anesthesia with halothane

Prophylactic treatment with beta blockers reduces mortality in post MI patients

SE sometimes causes or precipitates severe bradycardia Others drugs in this grp include: Sotalol and Esmolol

Amiodarone, is an unusual iodine containing highly lipophilic long acting antiarrhythmic actions. It prolongs both APD and ERP and slows conduction and automaticity

Blocks inactivated Na channels like lidocaine, inhibits myocardial Ca++ channels and has non competitive beta adrenergic blocking properties.

Kinetics, is incompletely and slowly absorbed from GIT, daily oral ingestion, the actions develops very slowly. On IV route action develops very fast.

It accumulates in muscles and fats and gets released slowly Metabolized in the liver and its duration of action is long 3-8 weeks Uses, widely used for ventricular and supraventricular arrhythmias.

However, because of its toxic potential its use has been limited to ventricular tachycardia and atrial fibrillations

Its long duration of action makes it suitable for long term prophylactic use but close monitoring is required

S/E of Amiodarone include fall in BP, and myocardial depression on IV injection, GIT effects, photosensitization and skin pigmentation occurs in 10% of pts, corneal microdeposits following long term use but are reversible on stopping the drug, pulmonary alveolitis and fibrosis are the most serious toxic effects, peripheral neuropahthy manifested by muscle weakness of shoulder and pelvic muscles, liver damage and interferes with thyroid function such conversion of T4 to T3, goitre, hypothyrodism and rarely hyperthyroidism may develop in chronic use

Interactions: the drug increases digoxin and warfarin levels by reducing their renal clearance

Also can cause additive a AV block in pts receiving beta blockers or calcium channel blockers

Other drugs: include Bretylium which is an adrenergic neurone blocker, previously used for controlling high BP but withdrawn because of poor oral absorption and development of tolerance

Verapamil, is a Ca++ channel blocker. It has the most prominent cardiac electrophysiological actions.

It depresses calcium mediated depolarization and this suppresses automaticity

It has antiarrhythmic activity as it decreases SA node and ventricular automaticity, no atrial and ventricular effects, but increases A-V nodal and ECG (P-R intervals) activities

Uses for PSVT is a drug of choice, Control of Ventricular rate in AF, Verapamil has poor efficacy in ventricular arrhythmias, in preventing recurrences

CIs: include watch for marked bradycardia, A-V block, cardiac arrest and hypotension should not be used if PSVT is accompanied with hypotension or CHF

Drugs for PARASUPRAVENTRICULAR TACHYCARDIA:

An attack of PSVT can be terminated by IV verapamil or diltiazem or propranolol or digoxin but now most cardiologist prefer Adenosines

However, maintenance therapy with oral digoxin, verapamil and other beta blockers can prevent recurrences

Adenosine is administered by rapid IV as a free base 6-12 mgs or as ATP 10-20 mgs.

It terminates within 30 secs more than 90% episodes of PSVT involving the A-V node

It activates Ach sensitive K channels and causes membrane hyperpolarization pacemaker depression leading to bradycardia

Adenosine has a very short half life in blood of about 10 secs

It is uptaken into RBCs and endothelial cells where it gets converted to 5-AMP and inosine

Complete elimination occurs in a single passage through coronary circulation.

Injected ATP is rapidly converted to adenosine

Dipyridamole potentiates its action by inhibiting uptake, while theophylline and caffeine antagonizes its action by blocking adenosine receptors

Higher doses of adenosine may be required in tea and coffee drinkers as it has similar stimulant effects.

Advantages of adenosine for termination of Paroxysmal Supravent Tachycardia (PSVT) are:

Better efficacy equivalent to or better than verapamil Rapid action less than 1 min (adverse effects such

as cardiac arrest) Has no haemodyanamic deterioration; can be given

to pts with hypotension, CCF, or those receiving beta blockers. Verapamil is C.I. in these conditions

Safe in wide QRS tachycardia. Verapamil is unsafe Effective in pts not responding to verapamil However, Adenosine has S/E like dyspnoea, chest

pain and flushing in 30-60% of pts

Other uses of Adenosine Diagnosis of taychcardias dependent on A-V node To induce brief coronary vasodilatation during

certain diagnostic/interventional procedures To produce controlled hypotension during surgery

Drugs for A-V Block Atropine; when A-V Block is due to vagal

overactivity e.g digitalis toxicity, some cases of MI, all these can be improved by atropine 0.6-1.2 mgs. Atropine increases conduction in the bundle of His

Sympathomimetics (e.g. adrenaline, isoprenaline). These overcome partial heart block by facilitating A-V conduction and shortening ERP of conducting tissues.

Choice of antiarryhythmics Simple arrhythmias e.g. Atrial Extrasystoles

(AES), and occasional ventricular extrasystoles VES

Rigorous therapy is indicated when: arrhythmia is life threatening e.g sustained VT; marked palpitations e.g PSVT, sustained VT; arrhythmias causing hypotention or CF; when simple arrhythmia may lead to more serious ones e.g after MI

Choice of an antiarrythmic in a patient depends on: ECG diagnosis Possible mechanism underlying the arrhythmia Mechanism of action and range of arrhythmic

activity of the drug Pharmacokinetic profile of the drug Haemodynamic effects of the drug

Note: the aim is to improve cardiovascular function either by restoring sinus rhythm or by controlling ventricular rate or by conversion to a more desirable pattern of electrical and mechanical activity.

Despite extensive investigations, the choice of an antiarrhythmic is still empirical (i.e. not definitive or still on experimental/on trials)