Antiarrhythmic drugs

History:

Although several of the drugs used to treat cardiac arrhythmias have been used for many years (e.g.- quinidine and digitalis since the early 1900s), most of the agents approved for use today have only been available for a decade or less.

Research in recent years has provided much information regarding the cellular mechanisms of arrhythmias and the mechanisms by which some of the antiarrhythmic drugs act, but the general approach to antiarrhythmic therapy remains largely empirical.

The recent results of several clinical trials, including the Cardiac Arrhythmia Suppression Trial (CAST), have indicated that many antiarrhythmic drugs may

significantly increase mortality compared to placebo.

Background:

All of the antiarrhythmic drugs act by altering ion fluxes within excitable tissues in the myocardium. The three ions of primary importance are Na+, Ca++, and K+. Antiarrhythmic drugs can be classified by their ability to directly or indirectly block flux of one or more of these ions across the membranes of excitable cardiac muscle cells.

9.1 Classification of Antiarrhythmic Drugs by Their Action:

Class I drugs, those that act by blocking the sodium channel, are subdivided into 3 subgroups, IA, IB, and IC based on their effects on repolarization and potency towards blocking the sodium channel.

Subclass IA drugs have high potency as sodium channel blockers (prolong QRS interval), and also usually prolong repolarization (prolong QT interval) through blockade of potassium channels.

Subclass IB drugs have the lowest potency as sodium channel blockers, produce little if any change in action potential duration (no effect on QRS interval) in normal tissue, and shorten repolarization (decrease QT interval).

Subclass IC drugs are the most potent sodium channel blocking agents (prolong QRS interval), and have little effect on repolarization (no effect on QT interval).

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Class II drugs act indirectly on electrophysiological parameters by blocking beta-adrenergic receptors (slow sinus rhythm, prolong PR interval, no effect on QRS or QT intervals).

Class III drugs prolong repolarization (increase refractoriness) by blocking outward potassium conductance (prolong QT interval), with typically little effect on the rate of depolarization (no effect on QRS interval).

Class IV drugs are relatively selective AV nodal L-type calcium-channel blockers (slow sinus rhythm, prolong PR interval, no effect on QRS interval).

Miscellaneous In addition to the standard classes, IA-C, II, III, and IV, there is also a miscellaneous group of drugs that includes digoxin, adenosine, magnesium, alinidine (a chloride channel blocker) and other compounds whose actions don't fit the standard four classes.

Table 1 Classification of Antiarrhythmic Drugs

Class Action Drugs

I Sodium Channel Blockade

IA Prolong repolarization Quinidine, procainamide, disopyramide

IB Shorten repolarization Lidocaine, mexiletine, tocainide, phenytoin

IC Little effect on repolarizationEncainide, flecainide, propafenone, moricizine

II Beta-Adrenergic Blockade Propanolol, esmolol, acebutolol, l-sotalol

III Prolong Repolarization (Potassium Channel Blockade; Other)

Ibutilide, dofetilide, sotalol (d,l), amiodarone, bretylium

IV Calcium Channel Blockade Verapamil, diltiazem, bepridil

Miscellaneous Miscellaneous Actions Adenosine, digitalis, magnesium

The metabolites of many of the drugs contribute to or are primarily responsible for their antiarrhythmic actions (e.g.- procainamide and its metabolite, N-acetylprocainamide; encainide and its metabolite, 3-methoxy-O-desmethylencainide)

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Pharmacology:

Antiarrhythmic drugs act by altering the flux of ions across the membranes of excitable cells in the heart. The primary mechanisms of action correspond to the mechanisms used in developing the and include inhibition of sodium channels (Class I drugs), inhibition of calcium channels (Class IV drugs), inhibition of potassium channels (Class III drugs), and blockade of beta-adrenergic receptors in the heart (Class II drugs).

Sodium Channel Blockade:

Sodium channels are responsible for the initial rapid (Phase 0) depolarization of atrial, Purkinje, and ventricular cells.

Sodium channel activation (opening) is voltage-dependent . The sodium current entering the cell during phase 0 depolarization is very intense,

but brief. Activation (opening) and inactivation (closing) of cardiac sodium channels is very

rapid. Blockade of sodium channels: o Slows the rate and amplitude of phase 0 depolarization oReduces cell excitability oReduces conduction velocity SA and AV nodal cells have relatively few sodium channels and therefore lack a

rapid phase 0 depolarization.

Calcium Channel (L-type) Blockade:

Calcium channels (L-type) are responsible for the prolonged plateau phase (Phase 2) seen in the action potential of atrial, Purkinje, and ventricular cells.

L-type calcium channel opening is voltage-dependent, but requires a more positive membrane potential than cardiac sodium channels.

The calcium current entering the cell during phase 2 is intense and prolonged. L-type calcium channels are slow to activate (open) and slow to inactivate (close). Blockade of calcium channels reduces the amplitude and length (time) of phase 2

in atrial, Purkinje, and ventricular cells. In SA and AV nodal cells, calcium entry through L-type channels represents the

major ion flux during depolarization.

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Potassium Channel Blockade:

Potassium channels, particularly the channel-giving rise to the "delayed rectifier current", are activated during the repolarization (Phase 3) of the action potential.

Blockade of potassium channels prolongs action potential duration. oProlongation of action potential duration usually results in an increase in effective

refractory period.

Use (Rate)-Dependent Blockade by Channel Blockers:

An ideal antiarrhythmic drug should target ectopic pacemakers and rapidly depolarizing tissue to a greater extent than normal tissues of the heart.

Many of the sodium (Class I) and calcium (Class IV) channel blockers have this property because they preferentially block sodium and calcium channels in depolarized tissues.

Enhanced sodium or calcium channel blockade in rapidly depolarizing tissue has been termed "use-dependent blockade" and is thought to be responsible for increased efficacy in slowing and converting tachycardias with minimal effects on tissues depolarizing at normal (sinus) rates.

Many of the drugs that prolong repolarization (Class III drugs, potassium channel blockers) exhibit negative or reverse rate-dependence.

oThese drugs have little effect on prolonging repolarization in rapidly depolarizing tissue.

oThese drugs can cause prolongation of repolarization in slowly depolarizing tissue or following a long compensatory pause, leading to repolarization disturbances and torsades de pointes.

Therapeutics:

It is often problematic to determine the best drug for a given patient due to the unknown etiology of many arrhythmias, patient-to-patient variability, and the multiple actions of many antiarrhythmic drugs. Three trial-and-error approaches are widely used:

o Empiric. That is, based upon the clinician's past experience. o Serial drug testing guided by electrophysiological study (EPS).

This invasive technique requires cardiac catheterization and induction of arrhythmias by programmed electrical stimulation of the heart, followed by a delivery of drugs to predict the most efficacious drug(s) to use for a given patient.

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o Drug testing guided by electrocardiographic monitoring (Holter monitoring). This noninvasive technique involves 24-hour recording of a patient's ECG before and during each drug treatment to predict optimal efficacy. The recent Electrophysiologic versus Electrocardiographic Monitoring (ESVEM) study concluded that there may not be any significant difference between the predictive value of this technique compared to programmed electrical stimulation.

Before beginning therapy: o Any factor that might predispose a patient to arrhythmias

(electrolyte abnormalities, hypoxia, proarrhythmic drugs, underlying disease states) should be eliminated

o A firm diagnosis should be made before beginning therapy and a baseline ECG should be established to monitor the efficacy of treatment

Monitoring during therapy should include: o Continuous and careful monitoring for efficacy and adverse effects o Monitoring plasma concentrations of drug, including free vs.

protein-bound because of the narrow therapeutic index of most antiarrhythmic drugs

Efficacy of Antiarrhythmic Drugs by Class:

Note that some drug classes (IA and III) are useful in treating both ventricular and supraventricular arrhythmias, whereas other drug classes (IB and IV) are usually only effective in treating either ventricular (Class IB) or atrial arrhythmias (Class IV).

Table 2 Relative Efficacies of Antiarrhythmic Drugs by Class:

Drug Class Efficacy

IA Atrial fibrillationVentricular arrhythmias

IB Ventricular arrhythmias

IC AV nodal reentry arrhythmias

Ventricular arrhythmias (can increase mortality despite suppressing PVCs)

II Atrial fibrillation/flutter (Ventricular arrhythmias)

III Atrial fibrillation/flutter Ventricular arrhythmias

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IV Atrial fibrillation/flutter Atrial automaticitiesAV AV nodal reentry

Adenosine AV nodal reentry Orthodromic tachycardia

Digitalis AV nodal reentry Atrial fibrillation/flutter

Magnesium Torsades de pointes

Table 3 Drugs of Choice for Cardiac Arrhythmias:

Arrhythmia(Links point to ECGs)

Drug of Choice(Non-drug therapy)

Alternatives(Non-drug therapy)

Atrial fibrillation/flutter

(Cardioversion) Verapamil, diltiazem, or beta-blocker to slow ventricular response

Digoxin to slow ventricular response Class IA, IC drugs for long-term suppression Ibutilide for termination Low dose amiodarone for prevention Dofetilide for prevention (RF ablation)

Other supraventricular tachycardias

Adenosine, Verapamil, or diltiazem for termination (RF ablation)

Class II drugs or digoxin for termination (Cardioversion or atrial pacing) Class IA, IC, II, or IV drugs or digoxin for long-term suppression

PVCs or non-sustained ventricular tachycardia

No drug therapy for asymptomatic patients

Class II drugs for symptomatic patients

Sustained ventricular tachycardia

(Cardioversion or chest thump is the safest and most effective treatment) Lidocaine for acute treatment

Procainamide, bretylium or amiodarone for acute treatment Sotalol, amiodarone, Class IA, IB, II, III can be used for long-term suppression

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(RF ablation or ICD)

Ventricular fibrillation

(Defibrillation is treatment of choice) Lidocaine to prevent recurrence

Amiodarone, procainamide or bretylium to prevent recurrence (RF ablation or ICD)

Digitalis-induced ventricular tachyarrhythmia

Digibind for life-threatening toxicity

Lidocaine Phenytoin Avoid cardioversion except for ventricular fibrillation Potassium (if hypokalemic)

Torsades de pointes

Magnesium sulfate

Remove causative agents Isoproterenol Potassium (if hypokalemic) (Cardiac pacing)

Adverse Effects of Antiarrhythmic Drugs:

Most of the antiarrhythmic drugs are associated with severe and sometimes life-threatening adverse effects.

A number of recent clinical trials (such as CAST) have demonstrated that many antiarrhythmic drugs increase mortality relative to placebo treatment.

The adverse effects of antiarrhythmic drugs can be categorized according to cardiac effects and extra-cardiac effects.

Adverse cardiac effects:

- Adverse cardiac effects are often predictable based on antiarrhythmic class.

- The most common and serious of adverse cardiac effects are proarrhythmias (a new or worsened rhythmic disturbance paradoxically precipitated by antiarrhythmic therapy) which can occur in 5-20% of patients treated with Class I and Class III drugs.

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Adverse extra-cardiac effects:

Severe extra-cardiac effects are also common with the antiarrhythmics and tend to be drug-specific.

Table 4 Adverse Extra-Cardiac Effects of Selected Antiarrhythmic Drugs:

Drug (Class) Adverse Extra-Cardiac Effects and Toxicities

Quinidine (IA)

GI disturbances in 30-50% of patients: diarrhea, nausea, vomiting Cinchonism Hypotension (due to alpha-adrenergic blocking activities) Can elevate serum digoxin concentrations, resulting in digitalis toxicity Hypersensitivity reactions: rashes, fever, angioneurotic edema, hepatitis Reversible thrombocytopenia

Procainamide (IA)

Hypotension (due to ganglionic blocking activity) Long-term use results in a lupus-like syndrome in 15-30% of patients consisting of arthralgia and arthritis (pleuritis, pericarditis, parenchymal pulmonary disease also occur in some patients) GI symptoms in 10% of patients Adverse CNS effects: giddiness, psychosis, depression, hallucinations Hypersensitivity reactions: fever, agranulocytosis (can lead to fatal infections), Raynaud's syndrome, myalgias, skin rashes, digital vasculitis

Lidocaine (IB)

Lowest incidence of toxicity of currently used antiarrhythmic drugs CNS depression: drowsiness, disorientation, slurred speech, respiratory depression, nausea CNS stimulation: tinnitus, muscle twitching, psychosis, seizures Concurrent use of tocainide or mexiletine can cause additive CNS toxicity, including seizures (seizures respond to i.v. diazepam)

Tocainide (IB)Mexiletine (IB)

GI effects: nausea, vomiting CNS effects: dizziness, disorientation, tremor Hematological effects (0.2%) with tocainide: agranulocytosis, bone marrow suppression, thrombocytopenia; can lead to death

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Concurrent use of either of these drugs and quinidine in combination may be effective at lower doses than either drug alone and thereby minimize adverse effects of both drugs

Flecainide (IC)

CNS effects in 10-15% of patients: dizziness, tremor, agitation, headache, visual disturbances GI upset

Amiodarone (III)

Although this drug is highly effective in treating many arrhythmias, its large number adverse effects limits its clinical use Adverse effects are common (more than 75% of patients receiving drug) and increase after a year of treatment; some toxicities result in death Half-life of 25-110 days can prolong toxicity Pulmonary toxicity and fibrosis (10-15%, can cause death in 10% of those affected); can be irreversible Constipation in 20% of patients) Hepatic dysfunction; can be irreversible Asymptomatic corneal deposits occur in all patients CNS effects (ataxia, dizziness, depression, nightmares, hallucinations) Hypothyroidism or hyperthyroidism (5% of patients) Cutaneous photosensitivity (25% of patients) and blue-grey discoloration of skin (less than 5% of patients) Peripheral neuropathy Substantial increases in LDL-cholesterol concentrations often seen; phospholipidosis Enhances the effect of warfarin and increases the serum concentrations of digoxin, quinidine, procainamide, flecainide, theophylline and other drugs

Digitalis (Misc.)

Many adverse non-cardiac effects (anorexia, nausea, vomiting, diarrhea, abdominal pain, headache, confusion, abnormal vision) Adverse effects may indicate digitalis toxicity

Adenosine (Misc.)

Short half-life in blood (less than 10 seconds) minimizes problems Causes hypotension, flushing in 20% of patients Transient dyspnea, chest discomfort (non-myocardial) in more than

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10% of patients Metallic taste Headache, hypotension, nausea, paresthesias are less common

Cinchonism: a syndrome associated with quinidine toxicity characterized by nausea, vomiting, diarrhea and a variety of CNS effects (tinnitus, headache, auditory and visual disturbances, and vertigo).

Amiodarone

Generic name: amiodarone

Brand name: Cordarone

Drug class and mechanism:

Amiodarone is used to correct abnormal rhythms of the heart (an antiarrhythmic medication).

Amiodarone is considered a "broad spectrum" antiarrhythmic medication, that is, it has multiple and complex effects on the electrical activity of the heart, which is responsible for the heart's rhythm. Among it’s most important electrical effects are:

1. A delay in the rate at which the heart's electrical system "recharges" after the heart contracts (repolarization);

2. A prolongation in the electrical phase during which the heart's muscle cells are electrically stimulated (action potential);

3. A slowing of the speed of electrical conduction (how fast each individual impulse is conducted through the heart's electrical system);

4. A reduction in the rapidity of firing of the normal generator of electrical impulses in the heart (the heart's pacemaker);

5. A slowing of conduction through various specialized electrical pathways (called accessory pathways), which can be responsible for arrhythmias.

In addition to being an antiarrhythmic medication, amiodarone also causes blood vessels to dilate (enlarge). This effect can result in a drop in blood pressure. Because of this effect it also may be of benefit in patients with congestive heart failure.

Uses:

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Amiodarone should be used for arrhythmias that are life threatening or that are very disruptive to one's life, and for which there are no other reasonable therapies.

When used appropriately, amiodarone can be a major benefit to patients. But because of the potential toxicity its use should be limited.

Dose:

Amiodarone usually is given in several daily doses to minimize stomach upset, which is seen more frequently with higher doses. For this same reason, it is also recommended that amiodarone be taken with meals.

Drug interactions:

Amiodarone may interact with beta- blockers such as atenolol (Tenormin), propranolol (Inderal), metoprolol (Lopressor), or certain calcium-channel blockers, such as verapamil (Calan, Isoptin, Verelan, Covera-HS) or diltiazem (Cardizem, Dilacor, Tiazac), resulting in an excessively slow heart rate or a block in the conduction of the electrical impulse through the heart.

Amiodarone increases the blood levels of digoxin (Lanoxin) when the two drugs are given together. It is recommended that the dose of digoxin is cut by 50% when amiodarone therapy is started.

Flecainide (Tambocor) blood concentrations increase by more than 50% with amiodarone. Procainamide (Procan-SR, Pronestyl) and quinidine (Quinidex, Quinaglute) concentrations increase by 30-50% during the first week of amiodarone therapy. Additive electrical effects occurs with these combinations, and worsening arrhythmias may occur as a result. Some experts recommend that the doses of these other drugs be reduced when amiodarone is started.

Amiodarone can result in phenytoin (Dilantin) toxicity because it causes a two- or three-fold increase in blood concentrations of phenytoin. Symptoms of phenytoin toxicity including unsteady eye movement (temporary and reversible), tiredness and unsteady gait.

Ritonavir (Norvir) can inhibit the enzyme that is responsible for the metabolism of amiodarone. Although no clinical problems have been recognized as a result of this interaction yet, it would be prudent to avoid this combination for fear of the potential for amiodarone toxicity.

Amiodarone also can interact with tricyclic antidepressants (e.g. amitriptyline, Elavil), or phenothiazines (e.g. chlorpromazine, Thorazine) and potentially cause serious arrhythmias.

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Amiodarone interacts with warfarin (Coumadin) and increases the risk of bleeding. The bleeding can be serious or even fatal. This effect can occur as early as 4-6 days after the start of the combination of drugs or can be delayed by a few weeks.

Features of amiodarone:

Amiodarone has several characteristics that make it unique. First, the drug takes weeks to achieve its maximum effectiveness. This is because

amiodarone is stored in most of the tissues of the body, and to "load" the body with the drug, all the tissues need to be saturated. The typical "loading" regimen of amiodarone, therefore, is to use very large doses for a week or two, then taper the dosage over the next month or so. It is not unusual to give patients 1200 or 1600 mg per day at first, and then maintain them on as little as 100 or 200 mg per day chronically.

Second, amiodarone leaves the body very, very slowly. It is not excreted (like most drugs) by the liver or the kidneys. It is lost when amiodarone-containing human cells are lost - such as skin cells or cells from the GI tract, which is shed by the millions each day. Thus, if it is decided that one needs to stop amiodarone, the drug remains in the body in measurable quantities for months and months. The "half life" of the drug, in contrast to most other drugs, is measured in weeks instead of hours.

Third, because amiodarone is stored in many different kinds of tissues, it can produce side effects affecting many different organs. Some of these side effects take months or years to develop, so it is never true that one can stop being vigilant.

Fourth, amiodarone works through many different mechanisms, unlike most drugs. It fits into two separate categories of antiarrhythmic drugs (Class I and Class III, for what it's worth). It acts as a beta-blocker and also as a calcium blocker. It dilates blood vessels, and and it often acts to "block" the effect of thyroid horomone.

The side effects of amiodarone:

The side effects of amiodarone often take weeks or months to develop so must be watched for as long as the drug is used.

Amiodarone commonly causes deposits to form on the cornea of the eyes - often leading to "halo-vision," where looking at bright lights at night is like looking at the moon on a foggy evening.

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Amiodarone can cause a very disfiguring blue-grey discoloration of the skin, generally in areas of sun exposure.

Amiodarone often sensitizes the skin to sunlight, so that even trivial exposure can cause fairly nasty sunburn.

Amiodarone can cause thyroid disorders, both hypothyroidism (low thyroid) and hyperthyroidism (high thyroid.) These thyroid problems are common with amiodarone, and can be unusually difficult to recognize and treat. For this reason, patients taking this drug should have their thyroid function routinely monitored.

Amiodarone can cause liver toxicity; so liver enzymes need to be monitored periodically. It can also cause rather severe gastric reflux.

The most serious side effect of amiodarone is pulmonary toxicity - lung disease. One form of lung problem caused by amiodarone is an acute pulmonary syndrome that looks and acts just like typical pneumonia - sudden onset of cough and shortness of breath. This condition usually improves rapidly once amiodarone is stopped. The second form is more insidious - it is a gradual, unnoticeable, "stiffening" of the lungs that both the doctor and patient can overlook until finally severe, probably irreversible lung damage is done.

Disopyramide

Mechanism:

The heart's pumping action is controlled by electrical signals, which pass through the heart muscle, causing contraction of the two pairs of heart chambers (left and right atria and ventricles). Disopyramide works by decreasing the sensitivity of heart muscle cells to electrical impulses, therefore slowing the electrical conduction in the heart muscle.

This helps to restore disturbances in heart rhythm (arrhythmias), which can seriously undermine the pumping action of the heart and result in inefficient blood circulation around the body.

Disopyramide is used to treat two forms of arrhythmia - ventricular and supraventricular arrhythmias, especially following heart attacks. It should be used with caution in all other types of arrhythmia.

It is given by intravenous infusion or by mouth in the form of capsules.

Uses:

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Irregular heart beats (arrhythmias)

Use with caution in,

Defect in the rate or frequency of messages in heart's electrical message pathway, resulting in decreased function of the heart (partial heart block)

Enlarged prostate (prostatic hypertrophy)

Glaucoma

Heart failure

Irregular heart beats (arrhythmias)

Kidney disease

Liver disease

Low blood sugar levels (hypoglycaemia)

Very low blood pressure (severe hypotension)

Contraindication:

Defect of the heart's electrical message pathways resulting in decreased function of the heart (heart block)

Loss of function of a natural pacemaker in the heart (sinus node dysfunction)

Severe heart failure

Very low blood pressure (severe hypotension)

Side effects:

Blurred vision

Difficulty in passing urine (urinary retention)

Dry mouth

Irregular heart beat (ventricular arrhythmias)

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Low blood glucose level (hypoglycaemia)

Low blood pressure (hypotension)

Yellowing of the skin and eyes (jaundice)

Blockade of the electrical pathways between the chambers of the heart (atrioventricular block)

Irritation to the lining or movements of the gut

Drug interaction:

There is an increased risk of myocardial depression (decreased impulses within the heart)

When used with the following: -

Other anti-arrhythmics Beta-blockers Calcium channel blockers, diltiazem and verapamil

The following drugs increase the risk of ventricular arrhythmias: -

Other anti-arrhythmics such as amiodarone Tricyclic antidepressants such as amitriptyline Terfenadine Halofantrine Thioridazine The antiviral ritonavir Sotalol Cisapride Rifampicin decreases the blood levels of disopyramide. Erythromycin and possibly clarithromycin increase the blood levels of

disopyramide. The risk of adverse effects on the heart is increased if disopyramide is taken with

diuretics, which cause a fall in blood potassium levels.

Lidocaine

Brand Name: Xylocaine

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Uses: This medication is used to treat irregular heartbeats (arrhythmias). This drug may also be used for resistant seizure treatment.

Dose: This medication is generally given by vein (IV). It may also be given in a large muscle (IM - in the shoulder usually) for one or two doses if necessary.

Side Effects: Unlikely but report promptly: drowsiness, dizziness, confusion, shakiness,

mental changes, ringing in the ears, visual changes, nausea, tingling or numbness, slurred speech, muscle twitching, unusually slow heartbeat, seizures.

Symptoms include: difficulty breathing, skin rash, itching, swelling.

Precautions: Before using this drug, tell your doctor your medical history, including:

allergies (especially drug allergies), heart problems, liver disease, and severe lung problems.

This medication should be used only when clearly needed during pregnancy. This drug is excreted into breast milk. Consult before breast-feeding.

Drug Interactions: Cimetidine Other drugs used for irregular heartbeats (arrhythmias) such as phenytoin,

procainamide, quinidine, and propranolol.

Procainamide

Mechanism:

Procainamide suppresses phase-4 depolarization in normal ventricular muscle and Purkinje fibers, reducing the automaticity of ectopic pacemakers. It also suppresses reentry dyrhythmias by slowing intraventricular conduction. Procainamide may be effective in treating PVCs and recurrent ventricular tachycardia that cannot be controlled with lidocaine.

Uses:

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Procainamide is indicated for ventricular dysrhythmias not controlled by Lidocaine. Procainamide is not a first drug of choice for treatment of ventricular dysrhythmias.

Dosage and Administration:

20 mg/min (30 mg/min for refractory VF): maximum dose is 17 mg/kg Maintenance infusion (after resuscitation from cardiac arrest) is 1-4 mg/min. For infusion, mix 2 grams of Procainamide in 500cc Normal Saline.

Adverse Reactions:

Contraindicated in the following, Second- and third-degree AV block, digitalis toxicity, and Torsades de pointes.

Special Considerations:

End Points to Procainamide administration are, suppression of arrhythmia, hypotension, widening of the QRS greater than 50% of original width, and maximum dose reached.

Quinidine Description Quinidine is used to treat a variety of arrhythmias including atrial fibrillation and ventricular tachycardia.

Mechanism:Quinidine regulates the flow of sodium into heart cells. Since the flow of sodium provides the basis for electrical signals in the heart, regulation of this flow can prevent irregular heart beats.

Precautions:

Notify your doctor if you have any kidney, liver or lung conditions before taking quinidine.

If you are pregnant or breastfeeding check with your doctor before taking quinidine.

Side Effects:

Fast or slow heart rate Lightheadedness, fainting or near fainting

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Nausea Tremor Loss of coordination Blue discoloration of the skin Amiodarone can lead to serious side effects in multiple organs including the

lung, liver and thyroid.

Drug Names:

Quinidine gluconate (Quinaglute®, Quinalan®)Quinidine sulfate (Quinidex Extentabs®)

Discussion of quinidine:

Quinidine has been in use for many years as an antiarrhythmic drug. It has been used for treatment of malaria in the past, and it is chemically identical, although orientated differently, to quinine, a common treatment for leg cramping.

Quinidine is available in two different preparations, quinidine gluconate and quinidine sulfate. The active drug is the same in both preparations. Quinidine is absorbed quite quickly with peak levels appearing in the blood about three to five hours after each dose. If quinidine is taken with food, the rate of absorption is faster.

Quinidine is classified as a class IA antiarrhythmic drug, meaning that one of its effects is to slow the rapid inward rush of sodium ions that is involved in activating heart muscle fibers. By slowing the ion flow, quinidine may make the heart less vulnerable to arrhythmias.

Its mechanism of action is undoubtedly, though, more complex than this. It is also known to effect ion channels other than sodium. Quinidine may terminate or prevent the occurrence of a number of cardiac arrhythmias including atrial fibrillation and flutter, as well as supraventricular tachycardia and ventricular arrhythmias. Most of its use, though, has been for atrial fibrillation.

It has been found that quinidine is more effective than dummy pills at restoring normal heart rhythm in patients in atrial fibrillation, and quinidine has also been found to be more effective at preventing relapses of atrial fibrillation after initial restoration of normal heart rhythm.

The safety of quinidine treatment is somewhat controversial. Quinidine was found in the older trials to be associated with a higher mortality than seen in patients treated with placebo pills. The increased mortality was small and the circumstances of these trials were quite different to current medical practice.

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Nevertheless, the safety of quinidine for long-term treatment has never been satisfactorily shown in properly designed trials.

Adverse Effects:

Like many other antiarrhythmic drugs, quinidine can provoke new lower chamber or ventricular arrhythmias of a particular type known as torsades de pointes.

Torsades is a life-threatening arrhythmia and can result in fainting spells or cardiac arrest, or sudden death. Risk of torsades is increased in patients with slow heart rates who are deficient in electrolytes such as potassium with evidence of prior ventricular arrhythmia.

A measurement on the electrocardiogram, the QT-interval, may help predict risk of this ventricular arrhythmia and needs to be monitored carefully in patients treated with quinidine and similar agents. The incidence of torsades in patients treated appropriately with quinidine is not known The incidence appears to be higher in patients who have serious heart diseases, particularly those associated with congestive heart failure.

Quinidine may cause a variety of other adverse effects also. At times when patients with atrial fibrillation or flutter are treated with quinidine, it may slow the rate of activity within the atrium but speed up conduction across the AV node or electrical connection between the atrium and ventricles causing the ventricular rate or pulse to become more rapid. This may result in a life-threatening ventricular or lower chamber arrhythmia and produce a fall in blood pressure or symptoms such as lightheadedness or fainting. In patients in whom the natural pacemaker of the heart is failing, quinidine may exacerbate that effect and cause excessive slowing of the heart rate.

Quinidine quite commonly can cause diarrhea and also has been associated with nausea, heartburn, fever, rash, ringing in the ears, vertigo, and a variety of other reactions. Rare cases of hepatitis, inflammation of the liver, have been described in patients taking quinidine. Quinidine may also activate the body's own immune system and cause immune-mediated symptoms such as hives, loss of blood platelets, and anemia amongst other conditions.

Drug Interactions:

Important drug interactions include those with amiodarone, other antiarrhythmic drugs, digoxin, warfarin, cimetidine, ketoconazole, phenytoin, and phenobarbital. It is thought that grapefruit juice may increase the blood levels of quinidine, although the significance of this is at present unknown.

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The usual dose of quinidine administered is 300 mg of quinidine gluconate or 324 mg of quinidine gluconate given every eight or twelve hours. If the pills are well tolerated, the blood level may be determined and the dose may be adjusted higher as considered necessary.

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