Antiarrhythmic drugs… an overview Peter Light Assistant Professor Dept of Pharmacology
Arrhythmias• Disturbances in ionic homeostasis can trigger arrhythmias• May be caused by genetic defects, ischemia, drugs and hormones• Ion channels control ionic balance and are therefore good targets for antiarrhythmic drugs
What is an arrhythmia? Fatal ventricular fibrillation leading to death
Arrhythmias• Treatment of the underlying disease e.g. CHF, mitral disease, WPW• Cardioversion (defibrillator)• Drugs There is no real “magic bullet”
Treating arrhythmias….• Surgical intervention• Implantable pacemakers and defibrillators• Drugs
Ion Flow and the Action Potential Na + Ca 2+ K+ (140 mM) (1.8 mM) (5 mM) outside inside Na + Ca2+ K+ (5 mM) (100 nM) (140 mM) Depolarizing Repolarizing
Antiarrhythmic drugs: Ideal properties • Good for all types of arrhythmia • Prevent reentry (one-way to two way block) • Increase refractory period • Block the effects of catecholamines • Reduce excitability • Little or no effects on contractility (inotropy) • Use-dependent block
The reality of anti-arrhythmic drugs• Must match the type of drug to the type of arrhythmia• The paradox: in the wrong circumstance drugs may actually trigger arrhythmias• “Therapeutic window” in many patients is small
Vaughan-Williams Classification Of Anti-arrhythmic Drugs Four main classes based on in vitro Electrophysiological Effects Atria, Purkinje fibre ventricle Fast AP SA/AV nodes Slow AP
Class 1 Anti-arrhythmicsCLASS 1A "Membrane stabilizers which prolong refractory period"CLASS 1B "Membrane stabilizers which reduce refractory period“CLASS 1C "Membrane stabilizers which slow depolarization”Class 1A e.g. Class 1B e.g. Class 1C e.g.Quinidine Lidocaine EncainideProcainamide Phenytoin FlecainideDysopyramide Mexiletine (rarely used now)
Class 1A Typical example: - Quinidine In the whole heart this leads to: • decreases in conduction velocity • decreases in automaticity • increases in refractory period • increased Q-T interval • conversion of one way block to two way block (abolishes re-entry) • increasing degree of block with more activity • decreases in contractility (negative inotropic effect)Used in atrial flutter/fibrillation. Nowadays class III agents are preferred asQuinidine has many side effects.
Class 1B Typical example: LidocaineDirect Effects on Cardiac Myocytes• blocks Na+ channels..increase threshold• only slows rate of rise of Phase 0 in damaged tissue (use-dependent effect)Important…….Use-dependence: The blocking action of the drug is more potentwhen ion channels are open ie. When more APs are firing.
Class 1B Typical example: LidocaineIn the whole heart this leads to:• decreases in automaticity especially in Purkinje Fibres• different effects on ischemic tissue vs healthy tissue• conversion of one way block to two way block in ischemic tissue• decreased APD (action potential duration) and ERP (effective refractory period).• little effect on contractility• little effect on ECG of healthy patients• good in acute situations eg. lidocaine in post-MI• good for ventricular arrhythmias but NOT supraventricular• short ½ life ~ 20 mins
CLASS IC Anti-arrhythmics "Membrane stabilizers" eg. Encainide, Flecainide.•Little “use dependence”•Bind more tightly, reaching a steady-state level•General reduction in excitability•Occasionally used for atrial fibrillation and tachycardias with abnormal conducting pathways•Not recommended post MI•To be used with discretion and can be pro-arrhythmic
CLASS II Anti-arrhythmics "Anti-adrenergics" (ß-adrenergic antagonists) eg. Propanolol and Metroprolol ß blocker and membrane stabilizer often used as an adjunct to other therapies. SA/AV node BUT contraindicated in: • acute heart failure • asthma (why?) • arrhythmias with A-V blockNote: Adrenaline can cause arrhythmias through effects on the pacemakerpotential and delayed after-depolarizations. Antagonism of the ß1-receptorsprevents this.
CLASS III Anti-arrhythmics "Prolong APD and ERP, no effect on rise time “ Potassium channel blockers Can have “reverse use- dependence” (with the exception of amiodarone)• Action on phase 3 of AP waveform• Delays repolarization, lengthens APD• Action on IKR,IKS current K channel sub-types
CLASS III Anti-arrhythmics Example: Amiodarone • prolongs refractory period • long duration of action (>30 days) • drug of choice in prevention of life-threatening ventricular arrhythmias..prophylactic or acute? • also used for atrial fibrillation/flutter • effective but “complex” profile - side effectsExample: Sotalol. ß-Blocker and Class IIIAnti-arrhythmic….prolongs APDUsed for severe VT and VF especially if patients can’ttolerate amiodarone
Seldane• Seldane (terfenadine), an anti-histamine OTC hay fever drug was withdrawn from market in 1997.Why?The pro-drug Terfanadine metabolized to the active metabolite fexofenadine byhepatic CYP3A4 activity (cytochrome P450-3A4).If CYP3A4 activity is inhibited then terfenadine levels rise. Terfenadine is a verygood inhibitor of IKr (HERG) current in the heart leading to TdP. Many antifungaland antibiotics inhibit CYP3A4.The active metabolite fexofenadineis now marketed as Allegra
CLASS 4 Anti-arrhythmics Eg.Verapamil and Diltiazem•`cardioselective Ca2+ channel blockers•block A-V conduction, useful in supra- ventricular arrhythmias• primarily effect SA/AV node APs- dangerous for ventricular arrhythmias ‘vascular selective Ca2+ channel blockers (ni***dipine/ dihydropyridines) are better vasodilators – NOT anti-arrhythmic agents Dose-selective block of vascular Calcium channels
Adenosine• occurs naturally• electrophysiological effects like ACh decreases sinus rate; decreases A-V conduction• useful for supraventricular tachycardias• also anti-ischemic• short t1/2Action of adenosine is throughThe A1 receptor directly coupled
Cardiac Glycosides (digitalis glycosides eg.. Digoxin) Digitalis, a drug prepared from digitalin, a glycoside obtained from the common foxglove, is used in medicine. With techniques of modern pharmacology, about a dozen steroid glycosides have been isolated from the leaves. The best known of these exert a twofold action on the heart that results in a more effective heartbeat. These medicines strengthen the force of contraction and, at the same time, slow the beat so that the period of relaxation between beats is lengthened. The heart muscle thus obtains more rest even though it is working harder.• acting on Na/K exchangers..(increased Nai)• therapeutic action of digitalis from its ability to slow A-V conduction via increases in vagal tone• used for atrial fibrillation• associated increases in contractility (CHF)
Toxicity of glycosides•Potentially fatal - common•Difficulty of diagnosis•Toxic dose = 2-3 x therapeutic dose•5-25 % of patients exhibit signs of toxicity•arrhythmias, enhancement of effects seen with therapeutic dose and generation of early and delayed afterdepolarizations (EADs and DADs).Best treatment is phenytoin (class 1B.)