CV PharmacologyAntiarrhythmicAgentsPresenter: Marc Imhotep Cray, M.D.Professor PharmacologyRecommended Reading:Antiarrhythmic DrugsFormative AssessmentPractice question set #1Clinical:E-Medicine ArticleVentricular FibrillationEKG TutorialRnCeus Interactive9/29/20092Electrophysiology and Cardiac Arrhythmias Cardiac RhythmNormal rate:60-100 beats per minuteImpulse Propagation:sinoatrial node atrioventricular (AV node) His-Purkinje distribution throughout the ventricle Normal AV nodal delay (0.15 seconds)--sufficient to allow atrial ejection of blood into the ventricles See Animated-Interactive Cardiac CycleHyper heartby Knowlege WeaversAdobe Shockwave Player9/29/20093Electrophysiology and Cardiac Arrhythmias(2)Definition:arrhythmia --cardiac depolarization different from previous slide sequence --abnormal origination (not SA nodal) abnormal rate/regularity/rhythm abnormal conduction characteristicsSee: http://www.rnceus.com/ekg/ekgframe.html9/29/20094Cardiac Electrophysiology The cardiac action potentialis a specialized action potential in the heart, with unique properties necessary for function of the electrical conduction system of the heartThe cardiac action potentialdiffers significantly in different portions of the heart This differentiation of action potentials allows different electrical characteristics of different portions of the heart For instance,the specialized conduction tissue of hearthas special property of depolarizing without any external influenceknown as cardiac muscle automaticitySee: Interactive animationillustrating the generation of a cardiac action potential9/29/20095Cardiac Electrophysiology(2)In cardiac myocytes, the release of Ca2+ from the sarcoplasmic reticulumis induced by Ca2+ influx into cell through voltage-gated calcium channelson the sarcolemmaThis phenomenon is called calcium-induced calcium releaseand increases myoplasmic free Ca2+ concentration causing muscle contraction9/29/20096Cardiac Electrophysiology(3)9/29/20097Cardiac Electrophysiology(4)Note that there are important physiological differences between nodal cellsand ventricular cells; the specific differences in ion channels and mechanisms of polarization give rise to unique properties of SA nodecells, most importantly the spontaneous depolarizations(cardiac muscle automaticity) necessary for the SA node's pacemakeractivity 9/29/20098Cardiac Electrophysiology(5)Calcium channelsTwo voltage-dependent calcium channelsplay critical roles in the physiology of cardiac muscle: 1.L-type calcium channel('L' for Long-lasting) and 2.T-type calcium channels('T' for Transient) voltage-gated calcium channelsThese channels respond differently to voltage changes across the membrane:L-type channels respond to higher membrane potentials, open more slowly, and remain open longer than T-type channelsAlso See Notes Page9/29/20099Cardiac Electrophysiology(6)The resting membrane potentialis caused by difference in ionic concentrations and conductances across the membrane of the cell during phase 4 of the action potential.The normal resting membrane potential in ventricular myocardium is about -85 to -95 mVThis potential is determined by the selective permeability of the cell membrane to various ionsThe membrane is most permeable to K+and relatively impermeable to other ions The resting membrane potential is therefore dominated by the K+ equilibrium potentialaccording to the K+ gradient across the cell membrane The cardiac action potential has five phases9/29/200910Cardiac Electrophysiology(7)The maintenance of this electrical gradient is due to various ion pumps and exchange mechanisms, including the Na+-K+ ion exchange pump, the Na+-Ca2+ exchanger currentRemember: Intracellularly K+is the principal cation, and phosphate and the conjugate bases of organic acids are the dominant anions.Extracellularly Na+and Cl-predominate9/29/200911Cardiac Electrophysiology(8)Transmembrane potential --determined primarily by three ionic gradients:Na+, K+, Ca 2+water-soluble, --not free to diffuse through the membrane in response to concentration or electrical gradients: depended upon membrane channels (proteins) Movement through channels depend on controlling "molecular gates"Gate-status controlled by:Ionic conditions Metabolic conditions Transmembrane voltage Maintenance of ionic gradients:Na+/K+ ATPase pump termed "electrogenic" when net current flows as a result of transport (e.g., three Na+ exchange for two K+ ions)9/29/200912Cardiac Electrophysiology(9)Initial permeability state --resting membrane potentialsodium --relatively impermeable potassium --relatively permeable Cardiac cell permeability and conductance:conductance: determined by characteristics of ion channel protein current flow = voltage X conductance voltage = (actual membrane potential -membrane potential at which no current would flow, even with channels open) 9/29/200913Cardiac Electrophysiology(10)SodiumConcentration gradient: 140 mmol/L Na+ outside: 10 mmol/L Na+ inside;Electrical gradient: 0 mV outside; -90 mV inside Driving force --both electrical and concentration --tending to move Na+ into the cell In the resting state:sodium ion channels are closed therefore no Na+ flow through the membrane In the active state:channels open causing a large influx of sodium which accounts for phase 0 depolarization 9/29/200914Cardiac Electrophysiology(11)Cardiac Cell Phase 0 and Sodium Current•Note the rapid "upstroke" characteristic of Phase 0 depolarization.•This abrupt change in membrane potential is caused by rapid, synchronous opening of Na+channels.•Note the relationships between the the ECG tracing and phase 0Source: http://www.pharmacology2000.com/Cardio/antiarr/antiarrtable.htm9/29/200915Cardiac Electrophysiology(12)Potassium:Concentration gradient (140 mmol/L K+ inside; 4 mmol/L K+outside) Concentration gradient --tends to drive potassium out Electrical gradient tends to hold K+ in Some K+ channels ("inward rectifier") are open in resting state --however, little K+ current flows because of the balance between the K+ concentration and membrane electrical gradients Cardiac resting membrane potential: mainly determined By the extracellular potassium concentration and Inward rectifier channel state9/29/200916Cardiac Electrophysiology(13)Spontaneous Depolarization (pacemaker cells)--phase 4 depolarizationSpontaneous Depolarization occurs because:Gradual increase in depolarizing currents (increasing membrane permeability to sodium or calcium)Decrease in repolarizing potassium currents (decreasing membrane potassium permeability) Both Ectopic pacemaker: (not normal SA nodal pacemakers) --Facilitated by hypokalemic states Increasing potassium: tends to slow or stop ectopic pacemaker activity 9/29/200917Cardiac Electrophysiology(14)Ca2+:Channel Activation Sequence similar to sodium; but occurring at more positive membrane potentials (phases 1 and 2)•Following intense inward Na+ current (phase 0), Ca2+currents:•Phases 1 & 2, are slowly inactivated.(Ca2+channel activation occurred later than for Na+)Source: http://www.pharmacology2000.com/Cardio/antiarr/antiarrtable.htm9/29/200918Cardiac Electrophysiology(15)Channel Inactivation, Re-establishing the Resting Membrane Potential•Final repolarization (phase 3):•complete Na+ and Ca2+ channel inactivation•Increased potassium permeability•Membrane potential approaches K+equilibrium potential --which approximates the normal resting membrane potentialSource: http://www.pharmacology2000.com/Cardio/antiarr/antiarrtable.htm9/29/200919Cardiac Electrophysiology(15)Five Phases:cardiac action potential associated with HIS-purkinje fibers or ventricular muscleSee Notes Page for Explainations9/29/200920Influence of Membrane Resting Potential on Action Potential PropertiesFactors that reduce the membrane resting potential & reduce conduction velocityHyperkalemiaSodium pump blockIschemic cell damage9/29/200921Influence of Membrane Resting Potential on Action Potential Properties(2)Factors that may precipitate or exacerbate arrhythmias IschemiaHypoxiaAcidosisAlkalosisAbnormal electrolytesExcessive catecholamine levelsAutonomic nervous system effects (e.g., excess vagal tone)Excessive catecholamine levelsAutonomic nervous system effects (e.g., excess vagal tone)Drug effects: e.g., antiarrhythmic drugs may cause arrhythmias)Cardiac fiber stretching (as may occur with ventricular dilatation in congestive heart failure)Presence of scarred/diseased tissue which have altered electrical conduction properties9/29/200922Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work? Anti-arrhythmic drugs may work by:(a) Suppressing initiation site (automaticity/after-depolarizations) and/or (b) Preventing early or delayed afterdepolarizations and/or (c) By disrupting a re-entrant pathway Reference Resource Reader:Teaching Cardiac Arrhythmias: A Focus on Pathophysiology and Pharmacology/PDF9/29/200923Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work? (a)Automaticity: Automaticity may be diminished by:(1) increasing the maximum diastolic membrane potential (2) decreasing the slope of phase 4 depolarization (3) increasing action potential duration (4) raising the threshold potential All of these factors make it take longer or make it more difficult for the membrane potential to reach threshold.(1) The diastolic membrane potential may be increased by adenosine and acetylcholine. (2) The slope of phase 4 depolarization may be decreased by beta receptor blockers (3) The duration of the action potential may be prolonged by drugs that block cardiac K+ channels (4) The membrane threshold potential may be altered by drugs that block Na+ or Ca2+ channels. 9/29/200924Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work?(b) Delayed or Early Afterdepolarizations:Delayed or early afterdepolarizations may be blocked by factors that(1) prevent the conditions that lead to afterdepolarizations. (2) directly interfere with the inward currents (Na+, Ca2+) that cause afterdepolarizations. 9/29/200925Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work?(c) ReentryFor anatomically-determined re-entry such as Wolf-Parkinson-White syndrome (WPW) drugs the arrhythmia can be resolved by blocking action potential (AP) propagationIn WPW-based arrhythmias, blocking conduction through the AV node may be clinically effectiveDrugs thatprolong nodal refractoriness and slow conduction include: Ca2+ channel blockers, beta-adrenergic blockers, or digitalis glycosides. 9/29/200926Intro to Arrhythmias and Drug Therapy(2)Atrial fibrillationmay result in a high ventricular following rateAtrial FibrillationAccordingly, drugs which may reduce ventricular rate by reducing AV nodal conduction include: 1.calcium channel blockers (verapamil (Isoptin, Calan), diltiazem (Cardiazem)) 2.beta-adrenergic receptor blockers (propranolol (Inderal)), and 3.digitalis glycosides 9/29/200927Arrhythmias and Drug Therapy (3)calcium channel blockersTreatment of atrial fibrillation(2)Verapamil (Isoptin, Calan) & Diltiazem (Cardiazem)Blocks cardiac calcium channels in slow response tissues, such as the sinus and AV nodes.Useful in treating AV reentrant tachyarrhythmias and in management of high ventricular rates secondary to atrial flutter or fibrillation. Major adverse effect (i.v. administration) is hypotensionHeart block or sinus bradycardia can also occur9/29/200928Arrhythmias and Drug Therapy (4)beta-adrenergic receptor blockersTreatment of atrial fibrillation:Propranolol (Inderal)Antiarrhythmic effects are due mainly to beta-adrenergic receptor blockadeNormally, sympathetic drive results in increased in Ca2+ ,K+ ,and Cl-currents 9/29/200929Arrhythmias and Drug Therapy (5)beta-adrenergic receptor blockersIncreased sympathetic tone also increases phase 4 depolarization (heart rate goes up), and increases DAD (delayed afterdepolarizations) and EAD (early afterdepolarization) mediated arrhythmiasThese effects are blocked by beta-adrenergic receptor blockers 9/29/200930Arrhythmias and Drug Therapy (6)beta-adrenergic receptor blockersBeta-adrenergic receptor blockers increase AV conduction time (takes longer) and increase AV nodal refractoriness, thereby helping to terminate nodal reentrant arrhythmias 9/29/200931Arrhythmias and Drug Therapy (7)beta-adrenergic receptor blockersBeta-adrenergic receptor blockade can also help reduce ventricular following rates in atrial flutter and fibrillation, again by acting at the AV node. 9/29/200932Arrhythmias and Drug Therapy (8)beta-adrenergic receptor blockersAdverse effectsof beta blocker therapy can lead to 1.fatigue, 2.bronchospasm, 3.depression, 4.impotence, 5.attenuation of hypoglycemic symptoms in diabetic patients6.worsening of congestive heart failure9/29/200933Class I Antiarrhythmic Drugs Class I: Sodium Channel BlockersSodium channel blocking antiarrhythmic drugs are classified as use-dependent in that they bind to open sodium channels Their effectiveness is therefore dependent upon the frequency of channel opening. 9/29/200934Class I Antiarrhythmic Drugs Type IaquinidineThere are three classes or types of sodium channel blockers:Type Ia: prototype:quinidinegluconate (Quinaglute, Quinalan Type Ia drugs slow the rate of AP rise and prolong ventricular effective refractory period9/29/200935Quinidine Overviewdextroisomer of quinine; quinidine gluconate (Quinaglute, Quinalan) also has antimalarial and antipyretic effects Pharmacokinetics:80%-90%: bound to plasma albumin Rapid oral absorption; rapid attainment of peak blood levels (60-90 minutes) Elimination half-life: 5-12 hoursIM injection, possible but not recommended due to injection site discomfort IV administration: limited due to myocardial depression & peripheral vasodilation 9/29/200936QuinidineMetabolism:Hepatic: hydroxylation to inactive metabolites; followed by renal excretion 20% excreted unchanged in urineImpaired hepatic/renal function: accumulation of quinidine and metabolites Sensitive to enzyme induction by other agents--decreased quinidine blood levels with phenytoin, phenobarbital, rifampin9/29/200937QuinidineMechanism of antiarrhythmic action--primarily activated sodium channel blockade which results in:Depression of ectopic pacemaker activity Depression of conduction velocitymay convert a one-way conduction blockade to a two-way (bidirectional) block --terminating reentry arrhythmias Depression of excitability (particularly in partially depolarized tissue) also see notes page9/29/200938QuinidineEffect on the ECG: QT interval lengtheningBasis: quinidine-mediated reduction in repolarizing outward potassium currentResult:Longer action potential durationIncreased effective refractory periodReduces reentry frequency; reduced rate in tachyarrhythmiasSodium channel blockade results inan increased threshold decreased automaticity9/29/200939QuinidineQuinidine Uses Used to manage nearly every form of arrhythmia especially acute and chronic supraventricular dysrhythmias Ventricular tachycardia Frequent indications:Prevent recurrence of supraventricular tachyarrhythmias Suppression ventricular premature contractions Approximately 20% of patients with atrial fibrillation will convert to normal sinus rhythm following quinidine treatment Supraventricular tachyarrhythmia due to Wolff-Parkinson-White syndrome --effective suppression by quinidine also see notes page9/29/200940QuinidineQuinidine Side EffectsCardiovascular--at (high) plasmaconcentrations (> 2ug/ml)Prolongation (ECG) of PR interval, QRS complex, QT interval Heart block likely with 50% increase in QRS complex duration (reduced dosage)Quinidine syncope:may be caused by delayed intraventricular conduction, resulting in ventricular dysrhythmia Patients with preexisting QT interval prolongation or evidence of existing A-V block (ECG): probably should not be treated with quinidine 9/29/200941QuinidineSide Effects (cont.)Quinidine is associated with Torsades de pointes, a ventricular arrhythmias associated with marked QT prolongationTorsades de pointes:Electrophysiological Features ventricular origin wide QRS complexes with multiple morphologies changing R -R intervals axis seems to twist about the isoelectric line This potentially serious arrhythmia occurs in 2% -8% if patients, even if they have a therapeutic or subtherapeutic quinidine blood level9/29/200942QuinidineSide Effects (cont.)Other quinidine adverse effects include:cinchonismblurred vision, decreased hearing acuity, gastrointestinal upset,headaches and tinnitus. Nausea, vomiting, diarrhea (30% frequency) Drug-drug interaction:quinidine gluconate (Quinaglute, Quinalan)-digoxin (Lanoxin, Lanoxicaps)Quinidine increases digoxin plasma concentration; may cause digitalis toxicity in patients taking digoxin or digitoxin 9/29/200943QuinidineSide Effects (cont.)Effects on neuromuscular transmission:Quinidine gluconate (Quinaglute, Quinalan) interferes with normal neuromuscular transmission; enhancing the effect of neuromuscular-blocking drugs Recurrence of skeletal muscle paralysis postoperatively may be associated with quinidine administration 9/29/200944Class I Antiarrhythmic Drugs Type IaProcainamideOverview:Local anesthetic (procaine) analog Long-term use avoided because of lupus-related side effect9/29/200945ProcainamideMetabolism:Elimination: renal excretion & hepatic metabolism; procainamide is highly resistant to hydrolysis by plasma esterases40%-60% excreted unchanged (renal) Renal dysfunction requires procainamide dosage reductionHepatic metabolism --acetylationcardioactive metabolite: N-acetylprocainamide (NAPA);NAPAaccumulation may lead to Torsades de pointes 9/29/200946ProcainamideQuinidine and Procainamide similar: electrophysiological propertiesPossibly somewhat less effective in suppressing automaticity; possibly more effective in sodium channel blockade in depolarized cells Useful in acute management of supraventricular and ventricular arrhythmias.Drug of second choice for management of sustained ventricular arrhythmias (in the acute myocardial infarction setting) Effective in suppression of premature ventricular contractions & paroxysmal ventricular tachycardia rapidly following IV administration 9/29/200947ProcainamideMost important difference compared quinidine:procainamide does not exhibit vagolytic (antimuscarinic) activityProcainamide is less likely to produce hypotension, unless following rapid IV infusionGanglionic-Blocking Activity9/29/200948ProcainamideSide Effects /ToxicitiesLong term use is associated with side effects, including a drug-induced, reversible lupus erythematosus-like syndromewhich occurs at a frequency of 25% to 50%.Consists of serositis, arthralgia & arthritis Occasionally: pluritis, pericarditis, parenchymal pulmonary disease Rare: renal lupus Vasculitis not typically present (unlike systemic lupus erythematosus) Positive antinuclear antibody test is common; symptoms disappear upon drug discontinuation In slow acetylators the procainamide-induced lupus syndrome occurs more frequently and earlier in therapy than in rapid acetylators. Nausea, Vomiting --most common early, noncardiac complication9/29/200949Class I Antiarrhythmic Drugs Type IaDisopyramide (Norpace)Overview:Very similar to quinidine gluconate (Quinaglute, Quinalan)Greater antimuscarinic effects(in management of atrial flutter & fibrillation, pre-treatment with a drug that reduces AV conduction velocity is required) Approved use(USA): ventricular arrhythmias9/29/200950Disopyramide (Norpace)Metabolism:Dealkylated metabolite (hepatic); less anticholinergic, less antiarrhythmic effect compared apparent compound 50% --excreted unchanged, renal Electrophysiological effects similar to quinidine gluconate (Quinaglute, Quinalan)Similar to quinidine gluconate (Quinaglute, Quinalan) in effective ventricular and atrial tachyarrhythmia suppression prescribed to maintain normal sinus rhythm in patients prone to atrial fibrillation and flutter and is also used to prevent ventricular fibrillation or tachycardia 9/29/200951Disopyramide (Norpace) Side Effects/ToxicityAdverse side-effect profile:different from qunidine's in that disopyramide (Norpace) is not an alpha-adrenergic receptor blockerbut is anti-vagalMost common side effects: (anticholinergic)dry mouth urinary hesitancy Other side effects:blurred vision, nausea 9/29/200952Disopyramide (Norpace) Side Effects/Toxicity (cont.)Cardiovascular:QT interval prolongation (ECG) paradoxical ventricular tachycardia (quinidine-like) Negative inotropism (significant myocardial depressive effects)--undesirable with preexisting left ventricular dysfunction (may promote congestive heart failure, even in patients with no prior evidence of myocardial dysfunction)Disopyramide is not a first-line antiarrhythmic agent because of itsnegative inotropic effectsIf used, great caution must be exercised in patients with congestive heart failure Can cause torsades de pointes, a ventricular arrhythmia 9/29/200953Class I Antiarrhythmic Drugs Type IbClass Ib agentsare often effective in treating ventricular arrhythmiasExample:lidocaineType Ib agentsexhibit rapid association and dissociation from the channel9/29/200954Class I Antiarrhythmic Drugs Type Ib (Class IB, Sodium Channel Blocker)Mexiletine (Mexitil)OverviewAmine analog of lidocaine (Xylocaine), but with reduced first-pass metabolism Suitable for oral administration Similar electrophysiologically to lidocaine9/29/200955Class I Antiarrhythmic Drugs Type Ib MexiletineClinical Use:Chronic suppression of ventricular tachyarrhythmias Combination with a beta adrenergic receptor blocker or another antiarrhythmic drug (e.g. quinidine gluconate (Quinaglute, Quinalan) or procainamide (Procan SR, Pronestyl-SR)): synergistic effects allow:reduced mexiletine dosage decreased side effect incidence9/29/200956Class I Antiarrhythmic Drugs Type Ib Mexiletine (Cont.)Possibly effective:decreasing neuropathic pain when alternative medications have proven ineffective--applications (on-label use):diabetic neuropathy nerve injury Side effects:Epigastric burning: usually relieved by a taking drug with food nausea (common) Neurologic side effects:diplopia, vertigo, slurred speech (occasionally), tremor 9/29/200957Class I Antiarrhythmic Drugs Type Ib (Class IB, Sodium Channel Blocker)Lidocaine (Xylocaine)Overview/Pharmacokinetics:Local anesthetic administered by i.v. for therapy of ventricular arrhythmias Extensive first-pass effect requires IV administration Half-life: two hours Infusion rate: should be adjusted based on lidocaine plasma levels MetabolismHepatic;some active metabolites 9/29/200958Lidocaine (Xylocaine)(Class Ib, Sodium Channel Blocker)Factors influencing loading and maintenance doses:Congestive heart failure(decreasing volume of distribution and total body clearance) Liver disease:plasma clearance --reduced; volume of distribution --increased; elimination half-life substantially increased (3 X or more) Drugs that decrease liver blood flow(e.g. cimetadine, propranolol), decreased lidocaine clearance (increased possible toxicity) 9/29/200959Lidocaine (Xylocaine)(Class Ib, Sodium Channel Blocker) (Cont.)Cardiovascular Effects:Site of Action: Sodium ChannelsBlocks activated and inactivated sodium channels (quinidine blocks sodium channels only in the activated state) No significant effect on QRS or QT interval or on AV conduction (normal doses) Lidocaine (Xylocaine) decreases automaticity by reducing the phase 4 slope and by increasing threshold 9/29/200960Lidocaine (Xylocaine) (Cont.)lidocaineis more effective in suppressing activity in depolarized, arrhythmogenic cardiac tissue but little effect on normal cardiac tissue --the basis for this drug's selectivityVery effective antiarrhythmic agent for arrhythmia suppression associated with depolarization(e.g., digitalis toxicity or ischemia)Comparatively ineffective in treating arrhythmias occurring in normally polarized issue (e.g., atrial fibrillation or atrial flutter) 9/29/200961Lidocaine (Xylocaine) (Cont.)Clinical Uses:Suppression of ventricular arrhythmias (limited effect on supraventricular tachyarrhythmias) May reduce incidence of ventricular fibrillation during the initial time frame following acute myocardial infarctionSuppression of reentry-type rhythm disorders:premature ventricular contractions (PVCs) ventricular tachycardia 9/29/200962Lidocaine (Xylocaine) (Cont.)Side Effect/ToxicitiesOverdosage:vasodilation direct cardiac depression decreased cardiac conduction --bradycardia; prolonged PR interval; widening QRS on ECG Major side effect --neurologicalLarge doses, rapidly administered can result in seizure.Factors that reduce seizure threshold for lidocaine:hypoxemia, hyperkalemia, acidosisOtherwise: CNS depression, apnea.9/29/200963Cardiac Electrophysiology Animations and Interactive TutorialsElectro Cardio Gramby Knowlege Weavers Interpeting an EKGEKG TutorialRnCeus InteractiveElectrocardiogram -ECG TechnicianNobel eMuseum Hyper heartby Knowlege Weavers The Arrhythma CenterHeartCenterOnline 9/29/200964Tocainide(Class I, Sodium Channel Blocker)TocainideAmine analog of lidocaine, similar to mexiletine, orally active --but with reduced first-pass metabolism. Used for chronic suppression of ventricular tachyarrhythmiasElectrophysiologically similar to lidocaine Similar to mexiletine: tocainide + beta-adrenergic receptor blocker or another antiarrhythmic drug: synergisme.g.--Combination with quinidine may increase efficacy and diminish adverse effects.9/29/200965Tocainide(Class I, Sodium Channel Blocker) (cont)Side Effects:Profile similar to mexiletine suitable for oral administration, but RARELY USED due to possibly fatal bone marrow aplasia and pulmonary fibrosistremor and nausea are major dose-related adverse side effects Excreted by the kidney, accordingly dose should be reduced in patients with renal disease 9/29/200966Free Useful PluginsAdobe Acrobat Reader-Document DistributionAdobe Flash Player-Web Animation -The leading rich client for Internet content and applications across the broadest range of platforms.Adobe Shockwave Player-With Adobe Shockwave Player, you can enjoy multimedia games and learning applications, using exciting new 3D technology.Adobe Authorware Player-With Adobe Authorware Web Player, you can experience online learning applications on the Web.QuickTime Player-Streaming/Multimedia9/29/200967Free Useful PluginsRealOne Player-Streaming/MultimediaMicrosoft Windows Media Player-Streaming/MultimediaMicrosoft Word Viewer-Viewing Word documents online (required if Word is not installed on resident computer; PC only)Microsoft PowerPoint Viewer-Viewing PowerPoint presentations online (required if PowerPoint is not installed on computer) Animated PowerPoint Add-in-needed if you do not have Office XPMicrosoft Excel Viewer-Viewing Excel documents online (required if Excel is not installed on resident computer; PC only)MDL Chimeinteractively displays 2D and 3D molecules directly in Web pages.