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Pharmacological Effects of Antiarrhythmic Drugs
Review and Update
Peter R. Kowey, MD
ost antiarrhythmic drugs are potent compounds with a relatively narrow therapeutic index. When prescribed judiciously, they can have a key role in enhancing or prolonging the lives of patients with most common arrhythmias. But when misprescribed, through selection of an inappropriate drug or dosage regimen, the end result may range from inadequate control of the arrhythmia to a proarrhythmic effect. Ultimately, the optimal use of antiarrhythmic drug therapy depends in large part on understanding the pharmacodynamics and pharmacokinetics of each antiarrhythmic drug. Despite the common classification of antiarrhythmic drugs into class I, II, III, or IV, each drug has a unique pharmacological profile and must not be considered interchangeable with other members of its class. Likewise, each patient is unique with respect to the innumerable factors that can alter the pharmacokinetics of an antiarrhythmic drug, including coexisting diseases, concurrent drug therapies, and endogenous or age-related metabolic variations. This article provides an overview of the key pharmacodynamic and pharmacokinetic characteristics of the major antiarrhythmic drugs in use. It also offers specific examples that may be used to ensure that patients receive the most appropriate therapy. Arch Intern Med. 1998;158:325-332
The optimal prescribing of antiarrhythmic drug therapy is predicated on a thorough understanding of the pharmacodynamics and pharmacokinetics for that drug. Numerous antiarrhythmic drugs are available, each of which has a unique pharmacological profile. A substantial percentage of the putative treatment failures seen in a consulting practice occur in patients who have not received the correct dosage of an antiarrhythmic drug or were treated with the incorrect drug. This underscores the importance of individualizing therapy to achieve the desired therapeutic effect. Many factors that must be considered when selecting an antiarrhythmic drug, including efficacy for the specific indication, relative toxicity, dosing convenience, and cost, apply to virtually any drug therapy. Other considerations that can influence the decision-making process are the familiarity of the practitioner with the drug, current treatment fads, previous exposure of the patient to the drug, and labeling concerns. However, the narrow therapeutic index of many antiarrhythmic drugs mandates careful consideration of such factors as whether the drug has active metabolites, whether coexisting diseases or concurrent drug therapy affect bioavailability, whether the drug is protein bound or undergoes first-pass (presystemic) metabolism, and potential drugdrug interactions (particularly with other antiarrhythmic drugs). These and other pharmacological properties of a drug can have profound implications for the clinical effectiveness and, more importantly, the clinical safety of a specific regimen. In some instances, lack of familiarity with the key pharmacodynamic and pharmacokinetic properties of an antiarrhythmic drug will not only compromise the therapeutic outcome but also can lead to serious, even lifethreatening, proarrhythmic effects.
From the Division of Cardiovascular Diseases, Lankenau Hospital and Medical Research Center, Wynnewood, Pa.
ARCH INTERN MED/ VOL 158, FEB 23, 1998 325
Downloaded from www.archinternmed.com on February 2, 2011 ©1998 American Medical Association. All rights reserved.
1998 326 rone) block the outward potassium current. thereby slowing the rate of the rise of the action potential. ↓. inward calcium current and thereby prolong the P-R interval without changing the QRS or Q-T interval. Downloaded from www. it is not a comprehensive or definitive source for prescribing antiarrhythmic drugs.4-6 it remains the clearest and most readily accessible method of categorizing the available antiarrhythmic drugs. and IC) primarily block the rapid inward sodium current.com on February 2. FEB 23. II. Although the Vaughan Williams1 classification system is a useful reference. verapamil hydrochloride and diltiazem hydrochloride) are primarily calcium channel– blocking agents. primarily because most antiarrhythmic drugs have more than one action. sotalol hydrochloride and amiodaARCH INTERN MED/ VOL 158. lidocaine hydrochloride. and toxic effects. flecainide acetate and propafenone hydrochloride) slow the conduction velocity but have little effect on repolarization. Hence. quinidine gluconate. Although numerous attempts have been made to revise and improve this classification system. The original system devised by Vaughan Williams1 includes 4 major groups of antiarrhythmic drugs: classes I. 2011 ©1998 American Medical Association.3 This article focuses on the general principles of pharmacology as they relate to antiarrhythmic drugs. intermediate kinetics potassium channel block Sodium channel block. they may increase the duration of the QRS and Q-T intervals. and IV. to a lesser extent. thus lengthening repolarization and refractoriness. it blocks potassium and sodium channels). Class II drugs (eg. which block the slow.lsotalol has class II and class III effects (ie. The pharmacodynamics of an antiarrhythmic drug determines not only the actions in specific arrhythmias but also the chronotropic. In addition. when prescribing antiarrhythmic drug therapy. ↑ P-R interval ↑ P-R interval. Adapted with permission from Siddoway. quinidine sulfate has class I and. a refinement that has increased the general usefulness of the Vaughan Williams1 classification system. class III effects (ie. elderly patients. the primary mechanism of action is based on their effects on certain ion channels and receptors located on the myocardial cell membrane. ↑ P-R interval ↑ Q-T interval Class Vaughan Williams IA Membrane Effect Sodium channel block. All rights reserved. propranolol hydrochloride and other -adrenergic blocking agents) are -adrenergic antagonists.archinternmed. PHARMACODYNAMICS AND CLASSIFICATION The pharmacodynamics of a drug refers to its mechanism of action and its effects at a specific site in the body. not just the drug class. Class IV drugs (eg. all of which can vary as a function of the site of action. For almost a quarter of a century. ↑P-R interval *↑ indicates increased. K+-ATPase inhibition Purinergic receptor agonist Examples of Drugs Quinidine Procainamide hydrochloride Disopyramide Lidocaine Tocainide Mexiletine hydrochloride Flecainide acetate Propafenone hydrochloride Moricizine Propranolol hydrochloride and others N-acetyl-procainamide Sotalol hydrochloride Amiodarone Ibutilide fumarate Verapamil Diltiazem hydrochloride Digoxin Digitoxin Adenosine IB IC II III IV Digitalis Adenosine ↓ Heart rate. tocainide hydrochloride. and patients with implantable cardioverterdefibrillators (ICDs). class IB drugs have a minimal effect on the QRS. Q-T. III.Table 1. it provides guidelines and recommendations for the use of antiarrhythmic drugs in the treatment of the overall patient population. procainamide hydrochloride. decreased. which slow the sinus rhythm and slow atrioventricular nodal conduction without substantially changing the Q-T or QRS interval. Class III drugs (eg. and disopyramide phosphate) prolong the repolarization and the refractoriness of isolated myocardial tissue in addition to blocking the rapid inward sodium current. and amiodarone exhibits the effects of all 4 classes. Class IB drugs (eg. or P-R interval. These potent sodium channel inhibitors increase the QRS interval more than the other class I drugs. In contrast to class IA drugs. slow kinetics -adrenergic receptor inhibition Potassium channel block. This article describes the marked pharmacological differences among antiarrhythmic drugs and emphasizes the importance of careful evaluation of the pharmacodynamic and pharmacokinetic characteristics of each drug. inotro- pic. an antiarrhythmic drug may have primary and secondary (or indirect) effects. For example. Thus. IB. . it blocks -adrenergic receptors and potassium channels). rapid kinetics Sodium channel block. understanding the different pharmacodynamic properties of these drugs is important to predict the antiarrhythmic effects in a patient. antiarrhythmic drugs have been differentiated by their antiarrhythmic action according to the wellknown classification system developed by Vaughan Williams1 and subsequently modified by Harrison2 (Table 1). slow sodium channel facilitator Calcium channel block Na+. ↓ Q-T interval ↓ Heart rate. Classification of Antiarrhythmic Drugs* Electrocardiographic Effect ↑ QRS and ↑ Q-T intervals ↓„ Q-T interval ↑↑ QRS interval ↓ Heart rate. The class I drugs were subclassified based on electrophysiologic effects. and mexiletine hydrochloride) shorten the action potential but produce only modest inhibition of the rapid inward sodium current. d. In addition. Drugs with class IA action (eg. For antiarrhythmic drugs. Drugs with class IC action (eg. Class I drugs (later subclassified as IA.
Metabolites of Antiarrhythmic Drugs Percentage Metabolized 99 20 40-60 8-28* 43-80† 95 80 98 50 99 85 50-70 99 Drug Amiodarone Bretylium tosylate Disopyramide Encainide hydrochloride Lidocaine Mexiletine hydrochloride Phenytoin Procainamide hydrochloride Propafenone hydrochloride Quinidine Tocainide Verapamil Major Metabolites N-desethylamiodarone None N-desisopropyl disopyramide O-desmethyl encainide and 3-methoxy-O-desmethyl encainide Monoethylglycine xylidide and glycine xylidide Para-hydroxymexiletine and hydroxymethylmexiletine‡ 5-Hydroxyphenyl phenyl hydantoin‡ N-acetyl-procainamide 5-Hydroxypropafenone 3-Hydroxyquinidine N-carboxy tocainide glucuronide and lactoxylidide‡ Norverapamil The pharmacokinetic profile of a drug describes the plasma level at a specific time after the administration of a dose. which lacks the class II ( -adrenergic blocking) properties of the parent compound. Table 4 gives an overview of the pharmacokinetic properties of the major antiarrhythmic drugs. it is essential to know which drugs have active metabolites when prescribing antiarrhythmic drug therapy. ARCH INTERN MED/ VOL 158. In addition. propafenone. electrolyte imbalance. On the other hand. PHARMACOKINETICS Table 2. Many antiarrhythmic drugs have active metabolites (Table 3) for which the action may be distinct from that of the parent drug. For example. Likewise. virtually none of the class II and III drug. by definition. the presence of coexisting disorders.com on February 2. but its major metabolite. Examples of Antiarrhythmic Drugs for Specific Indications* Indication Sinus tachycardia Sinoatrial reentrant tachycardia AV nodal reentrant tachycardia and AV reciprocating tachycardia (orthodromic) Termination Prevention Drug Propranolol hydrochloride Propranolol hydrochloride Verapamil IV verapamil IV diltiazem hydrochloride Verapamil Propranolol hydrochloride Propafenone hydrochloride Flecainide acetate Sotalol hydrochloride IV procainamide hydrochloride IV ibutilide fumarate Disopyramide Quinidine Propafenone Flecainide Sotalol Amiodarone Lidocaine IV procainamide hydrochloride IV amiodarone Propafenone Flecainide Sotalol Amiodarone Atrial fibrillation or flutter Termination Prevention Ventricular tachycardia Termination Prevention *AV indicates atrioventricular. 1998 327 ABSORPTION The bioavailability of a drug depends on the amount of the parent compound that reaches the systemic circulation. or high catecholamine levels. is a class III drug because it blocks the outward potassium channels and has little or no effect on the sodium channels. determining the therapeutic and undesirable effects of the drug.l-sotalol. intravenous. although no method exists to predict which patients are genetically predisposed to extensive or poor metabolism of a specific drug. the class IC drug. . ‡Inactive metabolites. These and other factors illustrate why the pharmacodynamic properties of a specific antiarrhythmic drug. distribution to various body tissues. is metabolized. Figure 1 shows the major pharmacokinetic events from the time of ingestion of an antiarrhythmic drug until elimination of the drug. Thus.Table 2 lists some common ar- rhythmias and examples of drugs from the Vaughan Williams1 classification system that might be useful for each arrhythmia. For example. N-acetylprocainamide. metabolism. Table 3. acidosis. †In persons in whom the drug undergoes excessive metabolism. procainamide hydrochloride is a class IA drug because it blocks sodium channels. in which the pharmacokinetic variables can have a critical role in *In persons with impaired metabolic ability.archinternmed. hypoxia. IV. such as ischemia. whereas the bioavailability of Downloaded from www. the bioavailability of an intravenously administered drug is. 100%. d. is metabolized to 5-hydroxypropafenone. should be the primary considerations when prescribing antiarrhythmic drugs. they are particularly relevant in antiarrhythmic drug therapy. Although these are important factors in the prescribing decisions for any drug. 2011 ©1998 American Medical Association. and elimination. FEB 23. rather than the class to which it belongs. The major factors that determine the plasma levels of a drug are the rate and extent of absorption. may also affect the pharmacodynamics of an antiarrhythmic drug. All rights reserved.
Many factors determine the volume of distribution of a drug. “deep” compartment composed of adipose tissue. The absorption of an antiarrhythmic drug can be reduced or the absorption time can be prolonged by the presence of certain foods (eg.0 µg/mL ...3 †Unless otherwise indicated. 2011 ©1998 American Medical Association... the bioavailability of D..7 DISTRIBUTION Metabolism in the Liver Absorption Dissolution Degradation Gut Lumen Clearance Pharmacogenetics Drug Interactions Diseases Elimination First Pass Plasma Kidney Heart Pharmacodynamics Ischemia Electrolytes Volume of Distribution Distribution Kinetics Protein Binding Other Tissues Figure 1.. 6-15 0. Adapted with permission from Siddoway. µmol/L† 1.5-2. antacids or cholestyramine) that bind the drug in the gastric lumen. In addition. 1998 328 Downloaded from www. Reprinted with permission from Siddoway.. liver.. No Yes . of Doses per Day 1 Infusion 1 1-4 2-3 2 Infusion Infusion 3 2-3 1 2-6 2-3 2-3 2 3 1-4 Target Plasma Level..0 8-17 6-13 16-24 3-5 3-8 4-17 10-20 8-20 3-7 Protein Binding.com on February 2. a drug enters the plasma and is distributed to a highly perfused “central” compartment consisting of organs such as the heart. 6. the presence of certain microflora in the gut can affect intraluminal drug degradation and thereby reduce the bioavailability of an antiarrhythmic drug.2-1.6-2. whereas the oral bioavailability of verapamil (20%-35%)..4-21. a theoretical concept that describes the relationship between the drug dose Table 4. 6. From there. muscle. ...... ‡Unless otherwise indicated.Lsotalol approaches 100%..an orally administered drug depends on factors related to absorption or to first-pass metabolism.5-2.. 90 35-45 50-70 70-85 25-75 60-80 90-100 100 20-35 Active Metabolites Yes No No Probable Yes No No Yes No Probable No Yes Yes Yes No No Yes *Intravenous form approved for antiarrhythmic use. and brain. Major Route of Elimination Hepatic Renal Renal Hepatic Renal and hepatic Renal Hepatic and renal Hepatic Hepatic Hepatic Hepatic Hepatic and renal Hepatic Hepatic Renal Renal and hepatic Hepatic Supplement After Hemodialysis No Yes No . FEB 23. and other tissues... 80-90 95 .6 nmol/L .4 0.4 0. No Yes ... Pharmacokinetic Properties of Antiarrhythmic Drugs* No.. kidney... % 96 10 20-30 70-80 50-65 40 . and sotalol are given in traditional units rather than SI units. 400-800 200-400 2 . and propafenone (25%75%) is low and variable.3 After absorption..25 .. 0.. All rights reserved. it is metabolized and eliminated or redistributed into a more slowly equilibrating. 60-80 70 95 90 20 90 80 0 50 90 Oral Bioavailability. so increased serum levels of digoxin resulted. skin. No Drug Amiodarone Bretylium* Digoxin Diltiazem hydrochloride* Disopyramide Flecainide acetate Ibutilide* Lidocaine* Mexiletine hydrochloride Moricizine Phenytoin Procainamide hydrochloride Propafenone hydrochloride Quinidine Sotalol hydrochloride Tocainide Verapamil Usual Daily Dosage.2-15.. . For example.. mexiletine. 450-750 600-900 200-400 2000-4000 450-900 600-1600 160-480 600-1800 240-480 Elimination Half-life. 55-75 . mg 200-400 .9 .0 µg/mL 16-57 . Yes No . 40-79 17-42 . eradicating the pathogen that had caused the reduced bioavailability.. This effect has been reported in some patients who initially required higherthan-normal doses of digoxin. toxic effects of digoxin developed when broad-spectrum antibiotics were administered. h‡ ∼53 d 4-16 36-48 4 6-9 20 6-9 1... 0.6-3. % 35-50 . Major pharmacokinetic events from drug ingestion to elimination....0 µg/mL . Table 5 lists some of the factors that can affect the bioavailability of an orally administered drug. milk) or drugs (eg. ARCH INTERN MED/ VOL 158..5-3. No Yes . Levels for flecainide. amiodarone (35%Administered Drug Drug Ingestion 50%)..archinternmed..
including quinidine. These include the ability of the drug to enter various tissues. and verapamil must be given in doses that are sufficiently high to compensate for their extensive first-pass metabolism. pH. anticoagulants. The elimination half-life is defined as the ARCH INTERN MED/ VOL 158. which interacts with virtually all drugs that are hydroxylated in the liver (eg. Evidence suggests that some persons have innately poor metabolic ability for specific drugs. All rights reserved.L-sotalol is devoid of protein binding. which may compromise hepatic metabolism and affect the elimination of hepatically metabolized drugs. Consequently. propranolol. a patient with congestive heart failure is likely to have decreased hepatic blood flow. FEB 23. the drug was prescribed for use up to 6 times daily. and the degree to which the drug is protein bound. Factors That May Alter the Bioavailability of an Oral Antiarrhythmic Drug* Factor Tablet dissolution. the plasma level of propafenone has been shown to increase 9fold after only a 3-fold increase in dosage. procainamide (15%). For example. whereas propafenone. and diltiazem. However. which simplifies their use. However. propafenone. 2011 ©1998 American Medical Association. which may enhance or diminish the plasma level of the drug. the metabolic fate is determined by genetic factors. mexiletine. Table 6 lists some common antiarrhythmic drugs and suggests dosing modifications for the treatment of patients with coexisting diseases or patients receiving digoxin or other commonly used drugs. and it is the unbound drug that exerts an electrophysiologic effect. which affects the dosage and route of administration. such as propafenone and amiodarone. some rapidly eliminated drugs are also metabolized in the plasma. vascular endothelium. Coingestion of other drugs. In contrast. It is interesting that most antiarrhythmic drugs used today. of which P4502D6 and P4503A4 are 2 of the most important. which was initially reported to have a half-life of only 3 to 5 hours. whereas drugs such as tocainide (10%). that encainide had at least 2 active metabolites that not only were more potent than the parent compound in causing a widened QRS interval and proarrhythmic effects but also had longer half-lives. formulation Physicochemical properties Gastric and bowel pH Bowel bacterial flora (intraluminal drug degradation) Intraluminal drug concentration Food Concomitantly administered drugs Bowel motility Bowel mucosal absorptive surface area Bowel wall circulation Presystemic Portal circulation blood flow (first-pass) Drug concentration in metabolism portal circulation Inherited metabolism phenotype Disease states (eg. requires intravenous administration because of its extremely poor systemic bioavailability when taken orally. Lidocaine.9 Another factor that can have an important role in biotransformation is coexisting disease. metoprolol tartrate. Clearance (ie. However. propafenone (90%). The issue of protein binding is particularly germane because many antiarrhythmic drugs are highly bound to plasma proteins. and D. the concept of half-life is complex because it reflects not only the half-life of the parent compound but also the half-life of any active metabolites. however. Antiarrhythmic drugs such as amiodarone (99%). the rate of removal of the drug from plasma) is the most dependable measure for determining the rates of drug metabolism and elimination. and the plasma level of the binding protein. For example. bretylium tosylate ( 10%). in a dose-dependent fashion. verapamil.L-sotalol do not interact pharmacokinetically with any other drugs. ELIMINATION The 2 most common routes of antiarrhythmic drug elimination are renal and hepatic. may also affect the metabolism of a specific compound. Another well-known and potentially serious interaction is the marked increase in serum digoxin levels produced by quinidine. flecainide. interactions with other drugs.Lsotalol (0%) are not. from 50% to 65% (Table 4). congestive heart failure or cirrhosis) Drug interactions that alter metabolism *Reprinted with permission from Siddoway. A number of antiarrhythmic drugs undergo extensive first-pass metabolism.com on February 2. Numerous other factors affect how an antiarrhythmic drug is metabolized. This is particularly true for amiodarone. blood cells. drugs such as D. It is commonly believed that a steady state is achieved after approximately 5 half-lives—about the same number of half-lives needed for elimination of a drug from the body.3 Absorption time needed for 50% of the drug to be eliminated from the body. for example. amiodarone.3. D. As a result. because a nonlinear increase usually occurs in the plasma levels when the oral dosage of antiarrhythmic drugs is increased. the lipophilicity. many patients who took encainide every 4 or 6 hours experienced serious proarrhythmic events as a result of massive accumulation of the metabolites. and lungs. In contrast. . 1998 329 Table 5. histamine2 blockers.archinternmed. steady-state levels can vary Downloaded from www. A dramatic illustration of this point was provided by the early clinical experience with encainide hydrochloride. including other antiarrhythmic drugs. interact with other widely used drugs.and plasma level expressed as a function of body weight. the protein binding of disopyramide can vary. METABOLISM The biotransformation (or metabolism) of most antiarrhythmic drugs occurs in the liver and is mediated by cytochrome P-450 isoenzymes. A complicating factor is the variable protein binding of antiarrhythmic drugs that can be influenced by the plasma level of the drug.8 The question of whether a drug possesses “saturable” kinetics must also be considered. For example. Protein binding can be increased or decreased. In many instances. and -adrenergic blocking agents). Investigators later discovered. and verapamil (90%) are almost completely metabolized.
Most antiarrhythmic drugs are eliminated by the liver (eg. . often leading to extensive drug accumulation. .. ±↑ Serum digoxin level .. . and digoxin)..... Recommended Dosing Modifications for Patients With Coexisting Disease or Who Are Receiving Other Drugs* Disease Drug Amiodarone Bretylium Digoxin Diltiazem hydrochloride Disopyramide Flecainide Ibutilide Lidocaine Mexiletine hydrochloride Moricizine Phenytoin Procainamide hydrochloride Propafenone hydrochloride Quinidine Sotalol hydrochloride Tocainide Verapamil Heart Failure ..... ....... .... Prystowsky.. Other drugs undergo hepatic and renal elimination (eg... because many putative drug “failures” can be attributed to the premature assessment of the effectiveness of the antiarrhythmic drug....... . Reprinted with permission from Eric N.. Problems may also arise when the route of elimination is not fully understood.... An example is procainamide... flecainide. . ±↓ Dosage . . ±↓ Dosage Cautious use . ↓ Dosage Avoid Avoid . As shown in Figure 2. and propafenone). ↑ Serum digoxin level Warfarin ↑↑ Protime . ↑ Serum digoxin level ↑↑ Serum digoxin level . .. For instance... and ↑.. more of an increase. procainamide. the effectiveness of procainamide can be assessed in 1 to 2 days compared with at least 7 days for amiodarone....3 half-lives. . .. Therefore.... . 1998 330 cians that steady-state levels of flecainide can be attained within 48 hours may be an underestimate... for many antiarrhythmic drugs....com on February 2. ↑ Dosage ..... decrease. and tocainide). is almost 95% bioavailable after only 3. ↓ Dosage ↓ Dosage . .L sotalol. . ↓ Dosage ↓ Dosage .. ↑↑. ↓. .. .... ↑ Dosage ... ↓ Dosage ↓ Dosage ↓ Dosage ↓ Dosage ... many patients who are referred because of an inadequate response to an antiarrhythmic drug may have been treated for an insufficient time for the drug to achieve a steady-state level.. . Bioavailability is a particularly important concept in antiarrhythmic drug therapy... Cautious use . ↑ Dosage ..... . ....... Cautious use Renal . ... ↓ Dosage ↓ Dosage ↓ Dosage ↓ Dosage ↓ Dosage ±↓ Dosage ↓ Dosage .. . lidocaine. increase.... Other risks are possible when it is erroneously assumed that a drug has achieved steady-state levels. tid. Hepatic ↓ Dosage . for example. . .. this interval varies widely from one drug to another. MD. . . . ↓ Dosage Digoxin ↑↑ Serum digoxin level . ↓ Dosage .... All rights reserved. .. . . waiting a “pharmacokinetically” appropriate period is essential before evaluating the response to treatment and changing the dosage.... . ↓ Dosage ±↓ Dosage . 2011 ©1998 American Medical Association. ↓ Dosage ↓ Dosage .... a patient who has received a specific antiarrhythmic drug and will undergo an examination in the electrophysiology laboratory or ambulatory monitoring. 3 times a day. In many cases.. 2 times a day. . dosage escalation is initiated if an adequate antiarrhythmic effect has not been demonstrated within the estimated time needed to reach a steady state... the assumption that bioavailability is the equivalent of 5 half-lives is not clinically relevant. whereas others are eliminated by the kidneys (eg.. .. as a function of clearance (which varies in the presence of factors such as hepatic or renal disease) and the dose of the drug. ±..Table 6.. . . for example... .. the assumption by cliniARCH INTERN MED/ VOL 158. Time from initiation of therapy to possible determination of effectiveness.. Drug Cimetidine .. ↑ Protime ±↓ Warfarin dosage .... FEB 23... and bid. quinidine. ±↑ Dosage (phenobarbital) *Ellipses indicate not applicable. The question of how much time must elapse from the time therapy is initiated until it is possible to determine effectiveness is dictated mainly by the time needed for the drug to reach steady-state levels. ........... Thus.. equivocal.. D. while its metabolites are Downloaded from www.. . ↑ Serum digoxin level . ↓ Dosage Phenytoin or Phenobarbital .. disopyramide. . For example. ↓ Dosage . ↓ Dosage . Consider.... Sotalol.... . . which is eliminated by the liver. the parent compound is eliminated by one route.3 Procainamide (qid) Quinidine (qid) Disopyramide (qid) Tocainide (tid) Mexiletine (tid) Sotalol (bid) Flecainide (bid) Encainide (tid) Amiodarone (bid) Minimum Maximum 0 1 2 3 4 5 6 7 8 9 10 Days Figure 2. Steady-state levels can also vary according to whether the drug has first-order kinetics.. . qid indicates 4 times a day.. whereas the active metabolite is eliminated by the other route. For some drugs.archinternmed.... ..... ↓ Dosage ↓ Dosage . . Thus. . Adapted with permission from Siddoway....
One reason for this dichotomy is that intravenous therapy produces excessive plasma levels of the parent compound. whereas others may be idiosyncratic or reflect variable individual susceptibility to a drug. volARCH INTERN MED/ VOL 158. the therapeutic range of most antiarrhythmic drugs is so wide that the concept of optimal plasma levels is virtually meaningless. for example. For propafenone. and drug metabolism. whereas the pharmacodynamics of a drug are affected by factors such as reduced density of and sensitivity to the -adrenergic receptors. In all of the aforementioned situations. Last. Furthermore. because the glomerular filtration rate is reduced substantially in elderly patients. 2011 ©1998 American Medical Association. The elimination kinetics of sotalol are among the least complicated. bretylium. lower dosages are required than would be used for younger patients. both of which are class III drugs that also have class II effects. flecainide. can be used to terminate monomorphic ventricular tachycardia (VT) in most patients when it is administered intravenously. ANTIARRHYTHMIC DRUG THERAPY FOR THE ELDERLY The pharmacological characteristics of virtually all drugs are affected by aging.L-sotalol and amiodarone. Although specific guidelines have not been established for antiarrhythmic drug therapy in the elderly.com on February 2. However. However. how- Downloaded from www. such substitutions may increase the risk of drugdrug or drug-device interactions. the judicious use of drug therapy in the elderly is a unique challenge. the comfort level of the prescribing physician with a specific antiarrhythmic drug regimen is often enhanced by tangible pharmacokinetic feedback. Thus. which does not have the same antiarrhythmic effects. Most studies. a change in formulation not only affects bioavailability of the drug but also may alter metabolism and elimination. One of the primary pharmacodynamic changes associated with aging is a reduction in -adrenoceptor sensitivity. All rights reserved. Some adverse effects are unrelated to the plasma level of the drug. a level that does not consider the additional activity of the active metabolite. FEB 23. whereas orally administered procainamide is metabolized to N-acetyl-procainamide. there would be valid grounds for determining the plasma level if symptoms recurred after discharge despite adequate control in the hospital. There may be a discrepancy between the drug prescribed in the hospital and that dispensed by the pharmacist. Problems are particularly apt to arise when a pharmacist substitutes a generic drug for a brand-name drug. particularly because of the widespread use of polypharmacy to treat an often bewildering array of coexisting diseases. but it is largely ineffective in preventing VT when administered orally. there is no evidence that aging necessarily alters the number or function of cardiac ion channels. because most acute situations resolve long before the test results are provided by the laboratory. such as propranolol. Many recommendations about antiarrhythmic drug therapy for the elderly apply to the use of any drug therapy in this age group. ANTIARRHYTHMIC DRUG THERAPY FOR PATIENTS WITH ICDs Reports about the percentage of patients with ICDs who are receiving concomitant antiarrhythmic drug therapy range from approximately 20% to 88%. PROS AND CONS OF MONITORING PLASMA LEVELS Considerable controversy surrounds the issue of monitoring plasma levels during administration of an antiarrhythmic drug. Thus. Of equal concern are situations in which a therapeutic regimen is changed from an intravenous to an oral formulation of the same drug. In addition. The pharmacokinetics of a drug are altered by age-related reductions in elimination by the kidneys. intravenous dosing ensures that the patient receives primarily the parent compound. to avoid drug-related toxic effects. the clinical relevance of plasma levels in the hospital setting is particularly doubtful. Lower dosages are especially important for antiarrhythmic drugs that are eliminated by the kidneys (eg. even if the relevance of this feedback is unclear.eliminated by the kidneys. quinidine gluconate is commonly substituted for quinidine sulfate. generally advisable practices are initiating therapy at a lower-than-recommended dosage and gradually titrating upward based on the patient’s tolerance of the drug. Furthermore. the end result is the same: there is no assurance that the patient is still receiving the same therapy that was successfully used to control the arrhythmia at the time of discharge from the hospital. Painstaking efforts have usually been made in the hospital to titrate the antiarrhythmic drug to achieve optimal therapeutic levels. Procainamide. and to ascertain that the formulation of the drug prescribed produces the desired effect. . it forms no metabolites and is eliminated exclusively by the kidneys. By its very nature. and digoxin). for example. legitimate reasons also exist for not monitoring plasma levels. 5-hydroxypropafenone. The main reasons for monitoring plasma levels are to confirm adherence to the therapeutic regimen. the therapeutic range for the plasma level of the parent compound is between 200 and 1500 ng/mL. class II antiarrhythmic drugs). IMPORTANCE OF THE DRUG FORMULATION IN DETERMINING PHARMACOKINETIC EFFECTS A major concern when prescribing antiarrhythmic drugs is that the pharmacokinetics of a drug can vary as a function of the formulation. For example. 1998 331 ume of distribution. Elderly patients also may be more susceptible to the effects of D. D. Because the pharmacokinetics of a drug are altered in elderly patients (primarily because of reduced renal and hepatic function and possibly reduced serum protein binding). the active metabolites are likely to have a more prominent role.archinternmed. because the antiarrhythmic properties or potential toxic effects of the 2 drugs may not be equivalent.L sotalol. which may lead to increased susceptibility to the effects of -adrenergic blocking agents (ie. when the same drug is administered orally.
1970:449-472. Wit AL. clinical experience suggests that even sophisticated third-generation ICDs do not obviate the need for antiarrhythmic drug therapy. Rund DG. 3. carefully evaluate the pharmacodynamics and pharmacokinetics of the antiarrhythmic drug and use objective criteria to determine the choice of therapies. In other words. Therefore. Is there a rational basis for the modified classification of antiarrhythmic drugs? In: Morganroth J. Thurer R. Harrison DC. Katzung BG. Vaughan Williams EM. Paracelsus wrote. Diagnosis.305:789-794. thereby decreasing the frequency of electric shocks and the amount of current required to terminate VT or ventricular fibrillation. several recommendations are proposed for optimizing the use of antiarrhythmic drug therapy.archinternmed. In this age of managed care. such as procainamide. Myerburg RJ. a poison. Lankenau Medical Office Building East. . Wayne. N Engl J Med. not by those of its class. considering not only the pharmacological properties of a specific antiarrhythmic drug but also such factors as the patient’s age. have a neutral or mixed effect. Second. Clinical experience with a tiered-therapy. Md: Williams & Wilkins. Luceri RM. Am Heart J. Interactions be¨ tween drugs and devices: experimental and clinical studies. 1992. The concomitant use of antiarrhythmic drugs and ICDs can prevent recurrent VT and slow sustained VT. In: Rosen MR. Mass: Nijhoff. 5. 2011 ©1998 American Medical Association.84:1831-1841. 1983. Siddoway LA. However. Janse MUJ. Time to first shock and clinical outcome in patients receiving an automatic implantable cardioverterdefibrillator. making it a theoretically attractive alternative for treating patients with hemodynamically stable VTs who have ICDs.472:373-381. Cardiac Arrhythmia: Mechanisms. Suite 556. Clinical pharmacologic requisites to ensure the adequacy of antiarrhythmic therapy. 1977. Lankenau Hospital and Medical Research Center. Last. 1989. Bigger JT Jr. CONCLUSION More than 400 years ago. antiarrhythmic drug therapy can be a useful adjunct for patients with ICDs. Troutman C. 2.L-sotalol may reduce the pacing and defibrillation thresholds. the clinical outcome of treatment with these potent drugs with potentially toxic effects should be positive. Moore EN. Flensted-Jensen E.” This maxim is particularly appropriate to the use of antiarrhythmic drugs. 1981. Jung W. 1984. 1990:1095-1115. Lindenbaum J. NY: Futura Publishing Co Inc. an economic incentive to use antiarrhythmic drug therapy also exists. 68:580-596. The slowing of VT may also increase the hemodynamic tolerance of VT and ease pace termination. Circulation. Am J Cardiol. and whether the patient takes other drugs or has an ICD. eds.com on February 2. 7. which is particularly prominent in class IC drugs. However. many available antiarrhythmic drugs increase defibrillation thresholds (and the current needed for defibrillation). and propafenone. Baltimore. multiprogrammable. eds. individualize therapy whenever possible. and Management. Circulation. bretylium. FEB 23. 12. Classification of antiarrhythmic drugs. Symposium on Cardiac Arrhythmias. The patient and therapy must be “matched” as closely as possible.ever. In: Sandoe E. using antiarrhythmic drugs as a first-line approach generally costs less than using invasive procedures. 1985:36-47. Third. coexisting disease. Kates RE. 4. Boston. Bardy GH. Others.127:978-984. Time. Circulation. All rights reserved. By observing these recommendations. D. ARCH INTERN MED/ VOL 158. Second. PA 19096. et al. Poole JG. First. Inactivation of digoxin by the gut flora: reversal by antibiotic therapy. 11. some drugs have a marked effect on pacing thresholds. For several reasons. 100 Lancaster Ave. thus prolonging or improving the quality of life for many patients. 1994. such as ablation or the implantation of defibrillators. Wynnewood. Connolly SJ. such as propafenone and flecainide. use drug combinations when appropriate and reasonable.5:8B-16B. Division of Cardiovascular Diseases. 1998 332 Downloaded from www.14:508514. Butler VP. Pharmacologic principles of antiarrhythmic drugs. Unlike many other classes of drugs (the members of which can be interchanged with relative impunity). et al. Olesen K II.10-12 Thus. Luderitz B. consider that multiple therapeutic options are available. Roden DM. the beneficial effects of antiarrhythmic drug therapy can readily be offset by the potential toxic effects when the drugs are prescribed without due regard for the appropriateness of a specific drug for a specific patient. Stockholm. for which the potential for remedial and toxic effects mandates a close appraisal of their pharmacodynamic and phar- macokinetic properties. In: Podrid PJ. antiarrhythmic drug therapy has an invaluable role in the treatment of most common arrhythmias. 8. Accepted for publication July 9. antiarrhythmia device. “A drug can be an inert substance. Cardiac Electrophysiology: A Textbook. Lebsack CS. Cardiac Arrhythmias: New Therapeutic Drugs and Devices. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. Kowey.and voltagedependent interactions of antiarrhythmic drugs with cardiac sodium channels. 10. Biochim Biophys Acta. 1997. Kowey PR. Dr Kowey is a consultant and speaker for Berlex Laboratories. The Sicilian gambit: a new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Clearly. 85:1689-1698. or a therapeutic agent dependent upon how it is used and the dosage in which it is given. et al. Reprints: Peter R. 9. Sweden: Astra. 1995:355-368. Antiarrhythmic treatment: an overview. Armonk. Hondeghem LM. Clinical pharmacology of propafenone. 6. J Am Coll Cardiol. 1991. NJ. MD. REFERENCES 1. Mainline Arrhythmia and Cardiology Consultants. 2 potentially important pharmacodynamic responses may occur when an antiarrhythmic drug is used with an ICD. Manz M. First. eds. the choice of antiarrhythmic drugs must be governed by due consideration of the unique characteristics of each drug. use pharmacological common sense when prescribing any antiarrhythmic drug. suggest that more than 50% of patients with ICDs also receive antiarrhythmic drugs. eds. especially in patients at risk for VT and atrial fibrillation.
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