Web viewA typical ECG is a repeating cycle of three electrical parts: a P wave ... In normal cardiac rhythm a p-wave precedes every QRS complex and the rhythm is

Arrhythmia & Anti-arrhythmic drugs: Dr. Mohammed Daoud

Cardiac pacemaker

The cardiac cells that create rhythmical impulses are called pacemaker cells, and they directly control the

heart rate. During each heartbeat, a healthy heart will have an orderly progression of depolarization (initiate

action potential ,i.e. electricity) that starts with pacemaker cells in the sinoatrial node (SA node), spreads out

through the atrium, passes through the atrioventricular node (AV node) down into the bundle of His and into

the Purkinje fibers spreading throughout the ventricles.

Electrocardiography (ECG)

Is the process of recording the electrical activity of the heart over a period of time using electrodes placed on

a patient's body. ECG can be used to measure the rate and rhythm of heartbeats and the effects of cardiac

drugs. A typical ECG is a repeating cycle of three electrical parts: a P wave (atrial depolarization), a QRS

complex (ventricular depolarization) and a T wave (ventricular repolarization).

In normal cardiac rhythm a p-wave precedes every QRS complex and the rhythm is generally regular. If this

is not the case, the patient may have a cardiac arrhythmia. Furthermore, any disturbance in the waves and

intervals (in above figure) cause arrhythmia.

* In adult , a heart rate between 60 and 100 beats per minute is considered normal. A heart rate slower than

60 beats per minute is said to be bradycardic and a rate faster than 100 beats per minute is said to be

tachycardic.

Cardiac arrhythmias occur as a result of Abnormal automaticity (if cardiac sites other than the SA node

show enhanced automaticity, they may generate competing stimuli) or from abnormalities in impulse

conduction or from both.

Abnormalities in impulse conduction: Impulses from higher pacemaker centers are normally conducted

down pathways that bifurcate to activate the entire ventricular surface (Figure). A phenomenon called reentry

can occur if a unidirectional block ( caused by myocardial injury) results in an abnormal conduction pathway.

This short-circuit pathway results in re-excitation of the muscle, causing premature contraction or sustained

arrhythmia. Reentry is the most common cause of arrhythmias, and it can occur at any level of the cardiac

conduction system.

Examples of common types of arrhythmia as appear in ECG are the following (figure):

Normal ECG

So in essence arrhythmia results from disturbance in cardiac electricity and diagnosed with

ECG. So treating arrhythmia needs to correct or repair these disturbance in cardiac electricity.

Understanding action potential is the key of understanding the mechanism of antiarrhythmic

drugs.

Generation of action potentials

The cardiac action potential is a short-lasting event in which the membrane potential (the difference of

potential between the interior and the exterior) of a cardiac cell rises and falls automatically.

*Note: The time between phase 0 and phase 3 is the refractory period.

Antiarrhythmic drugs:All antiarrhythmic drugs directly or indirectly alter membrane ion conductances, which in turn alters the

physical characteristics of cardiac action potentials.

Classes of Drugs Used to Treat Arrhythmias:

1. Class I: sodium channel blockers.

2. Class II: β- blockers.

3. Class III: Potassium channel blockers.

4. Class IV: cardiac calcium channel blockers.

5-Miscellaneous antiarrhythmic agents.

1. Class I: sodium channel blockers: The use of sodium channel blockers has been declining due

to their possible proarrhythmic effects;

A-PROCAINAMIDE: By blocking sodium channels, procainamide slows the upstroke of the action

potential, thus, slows conduction, and prolongs the QRS duration of the ECG.

Pharmacokinetics

Procainamide can be administered safely by intravenous and intramuscular routes and is well absorbed orally.

A metabolite ( N -acetylprocainamide, NAPA) has class III activity. Procainamide is eliminated by hepatic

metabolism to NAPA and by renal elimination. Its half-life is only 3–4 hours, which necessitates frequent

dosing or use of a slow-release formulation (the usual practice).

Toxicity

Procainamide’s cardiotoxic effects include excessive action potential prolongation and induction of torsades

de pointes arrhythmia and syncope.

A troublesome adverse effect of long-term procainamide therapy is a syndrome resembling lupus

erythematosus and usually consisting of arthralgia and arthritis.

Other adverse effects include nausea and diarrhea (in about 10% of cases), rash, fever, hepatitis (< 5).

Note: Torsades de Pointes is a type of ventricular tachycardia that can be the result of lengthening the QT

interval.

B- QUINIDINE:

Quinidine has actions similar to those of procainamide: it slows the upstroke of the action potential, slows

conduction, and prolongs the QRS duration of the ECG, by blockade of sodium channels.

Pharmacokinetics

Quinidine is readily absorbed from the GI tract and eliminated by hepatic metabolism. It is rarely used

because of the availability of better-tolerated antiarrhythmic drugs.

Toxicity

Excessive QT-interval prolongation and induction of torsades de pointes arrhythmia.

Diarrhea, nausea, and vomiting are observed in one third to one half of patients.

A syndrome of headache, dizziness, and tinnitus (cinchonism) is observed at toxic drug concentrations.

Idiosyncratic or immunologic reactions, including thrombocytopenia, angioneurotic edema are observed

rarely.

C- DISOPYRAMIDE:

The effects of disopyramide are very similar to those of procainamide and quinidine.

Pharmacokinetics Disopyramide is only available for oral use. Because of the danger of precipitating heart

failure, loading doses are not recommended.

Toxicity

Toxic concentrations of disopyramide can precipitate all of the electrophysiologic disturbances and thus

disopyramide is not used as a first-line antiarrhythmic agent .

It should not be used in patients with heart failure.

Disopyramide’s atropine-like activity accounts for most of its symptomatic adverse effects: urinary retention

(most often, but not exclusively, in male patients with prostatic hyperplasia), dry mouth, blurred vision,

constipation, and worsening of preexisting glaucoma.

D- LIDOCAINE :

Lidocaine has a low incidence of toxicity and a high degree of effectiveness in arrhythmias associated with

acute myocardial infarction. Lidocaine is the agent of choice for termination of ventricular tachycardia and

prevention of ventricular fibrillation in the setting of acute ischemia.

Pharmacokinetics

Because of its extensive first-pass hepatic metabolism, only 3% of orally administered lidocaine appears in

the plasma. Thus, lidocaine must be given parenterally. Lidocaine has a half-life of 1–2 hours. In adults, a

loading dose of 150–200 mg administered over about 15 minutes (as a single infusion or as a series of slow

boluses) should be followed by a maintenance infusion of 2–4 mg/min to achieve a therapeutic plasma level

of 2–6 mcg/mL.

In patients with liver disease, plasma clearance is markedly reduced; the elimination half-life in such cases

may be increased threefold or more.

Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase

the risk of toxicity unless infusion rates are decreased.

Renal disease has no major effect on lidocaine disposition.

Toxicity

Paresthesias, tremor, nausea of central origin, lightheadedness, hearing disturbances, slurred speech, and

convulsions. These occur most commonly in elderly or when a bolus of the drug is given too rapidly. The

effects are dose-related and usually short-lived.

Seizures which respond to intravenous diazepam.

Lidocaine is well tolerated.

E- MEXILETINE

Mexiletine is an orally active congener of lidocaine (by pass first pass effect). Its electrophysiologic and

antiarrhythmic actions are similar to those of lidocaine.

Pharmacokinetics

by pass first pass effect so active orally (unlike lidocaine). The elimination half-life is 8–20 hours and permits

administration two or three times per day. The usual daily dosage of mexiletine is 600–1200 mg/d.

Toxicity

Dose-related adverse effects are seen frequently at therapeutic dosage.

Tremor, blurred vision, and lethargy. Nausea is also a common effect.

*Mexiletine has also shown significant efficacy in relieving chronic pain, especially pain due to diabetic

neuropathy and nerve injury.

F- FLECAINIDE

Flecainide is a potent blocker of sodium and also potassium channels (Class III effect) .

Flecainide is very effective in suppressing premature ventricular contractions.

Pharmacokinetics

Flecainide is well absorbed. Elimination is both by hepatic metabolism and by the kidney.

Toxicity

It may cause severe exacerbation of arrhythmia even when normal doses are administered .

2. Class II: β- blockers (potential membrane stabilizing effect)Because sympathetic activity can precipitate arrhythmias through exciting cardiac cell membrane potential

(phase 4), drugs that block beta1-adrenoceptors are used to inhibit sympathetic effects on the heart. Esmolol

is a short-acting β blocker used primarily as an antiarrhythmic drug for intraoperative and ectopic beats.

3. Class III: Potassium channel blockers.by blocking potassium channels in cardiac muscle, these drugs prolong action potentials through prolonging

the effective refractory period.

A-AMIODARONE

Amiodarone is approved for oral and intravenous use to treat serious ventricular arrhythmias, supraventricular

arrhythmias and atrial fibrillation. As a result of its broad spectrum of antiarrhythmic action, it is very

extensively used for a wide variety of arrhythmias.

Pharmacokinetics

-It undergoes hepatic metabolism, and the major metabolite, desethylamiodarone, is bioactive. Therefore, The

elimination half-life is complex; After discontinuation of the drug, effects are maintained for 1–3 months.

- The drug accumulates in many tissues, including the heart (10–50 times more so than in plasma), lung, liver,

and skin, and is concentrated in tears. Measurable tissue levels may be observed up to 1 year after

discontinuation since the drug .

A total loading dose of 10 g is usually achieved with 0.8–1.2 g daily doses. The maintenance dose is 200–400

mg daily.

Toxicity

1-The drug accumulates in many tissues, including the heart (10–50 times more so than in plasma), lung,

liver, and skin, and is concentrated in tears.

-Amiodarone may produce symptomatic bradycardia in patients with AV node disease.

-Dose-related pulmonary toxicity is the most important adverse effect.

-Abnormal liver function tests and hypersensitivity hepatitis may develop and liver function tests should be

monitored regularly.

-The skin deposits result in a photodermatitis and a gray-blue skin discoloration in sun-exposed areas.

- Asymptomatic corneal microdeposits are present in virtually all patients treated with amiodarone but drug

discontinuation is usually not required.

2-Amiodarone is a potential source of large amounts of inorganic iodine. It blocks the peripheral conversion

of thyroxine (T 4 ) to triiodothyronine (T 3 ). It may result in hypothyroidism or hyperthyroidism. So, thyroid

function should be evaluated before initiating treatment and should be monitored periodically.

Drug interactions

-Amiodarone has many important drug interactions, and all medications should be reviewed when the drug is

initiated and when the dose is adjusted. Amiodarone is a substrate for liver cytochrome CYP3A4, and its

levels are increased by drugs that inhibit this enzyme, eg, cimetidine. Drugs that induce CYP3A4, eg,

rifampin, decrease amiodarone concentration when coadministered.

-Amiodarone inhibits several cytochrome P450 enzymes and may result in high levels of many drugs,

including statins, digoxin, and warfarin. The dose of warfarin should be reduced by one third to one half

following initiation of amiodarone and prothrombin times should be closely monitored.

B- DRONEDARONE

Dronedarone is a structural analog of amiodarone in which the iodine atoms have been removed . The design

was intended to eliminate action of the parent drug on thyroxine metabolism and to modify the half-life of the

drug. No thyroid dysfunction or pulmonary toxicity has been reported. However, liver toxicity has been

reported. Dronedarone elimination is primarily non-renal. However, it inhibits tubular secretion of creatinine,

resulting in a 10–20% increase in serum creatinine.

C- SOTALOL

Sotalol has both membrane stabilizing (phase 4) through β-adrenergic receptor-blocking (class 2) and action

potential-prolonging (class 3) actions.

Pharmacokinetics:

The drug is formulated as a racemic mixture of D- and L-sotalol. It is not metabolized in the liver and is not

bound to plasma proteins. Excretion is predominantly by the kidneys in the unchanged form with a half-life

of approximately 12 hours.

Toxicity

Its most significant cardiac adverse effect is an extension of its pharmacologic action: a dose-related

incidence of torsades de pointes that approaches 6% at the highest recommended daily dose. Sotalol is

approved for the treatment of life-threatening ventricular arrhythmias and the maintenance of sinus rhythm in

patients with atrial fibrillation. It is also approved for treatment of supraventricular and ventricular

arrhythmias in the pediatric age group.

D- DOFETILIDE

E- IBUTILIDE

4. Class IV: Cardiac calcium channel blockers:Verapamil and diltiazem have antiarrhythmic effects. The dihydropyridines (eg, nifedipine) do not share

antiarrhythmic efficacy and may precipitate arrhythmias.

A-VERAPAMIL

Verapamil blocks L-type calcium channels.. Supraventricular tachycardia is the major arrhythmia indication

for verapamil.Verapamil can induce AV block when used in large doses or in patients with AV nodal disease.

The half-life of verapamil is approximately 7 hours. It is extensively metabolized by the liver. Therefore,

verapamil must be administered with caution in patients with hepatic dysfunction or impaired hepatic

perfusion.

B-Diltiazem appears to be similar in efficacy to verapamil in the management of supraventricular

arrhythmias.

5-Miscellaneous antiarrhythmic agents.Certain agents used for the treatment of arrhythmias do not fit the conventional class 1–4 organization. These

include:

1- Digitalis :because of thier ability to activate the vagus nerve (parasympathomimetic effect), they slow the

rapid AV conduction velocity that occur during atrial flutter or fibrillation.

2- Atropine, a muscarinic receptor antagonist; because of thier ability to inhibit the vagus nerve

(parasympatholytic effect), they increase the slow AV conduction velocity that occur during beta-blocker

overdose.

3- Magnesium: Magnesium therapy appears to be indicated in patients with digitalis-induced arrhythmias if

hypomagnesemia is present. The usual dosage is 1 g (as sulfate) given intravenously over 20 minutes and

repeated if necessary.

4-Potassium: Because both Hypokalemia and Hyperkalemia is potentially arrhythmogenic, potassium

therapy is used in Hypokalemia toward normalizing potassium level in the body. Whereas Hypokalemia

treatment involve giving glucose together with soluble insulin. Endogenous insulin, stimulated by a glucose

load or administered intravenously, stimulates intracellular potassium uptake, thus removing it from the

serum.