Antiarrhythmic drugs p_light

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

There is no real “magic bullet”

• Treatment of the underlying disease e.g. CHF, mitral disease, WPW

• Cardioversion (defibrillator)

• Drugs

Treating arrhythmias….

• Surgical intervention

• Implantable pacemakers and defibrillators

• Drugs

Ion Flow and the Action Potential

K+

(140 mM)

Na +

(140 mM)K+

(5 mM)

Na +

(5 mM)

Ca2+

(1.8 mM)

Ca2+

(100 nM)

outside

inside

Depolarizing Repolarizing

Ion channels and theAction potential

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

Slow AP

Fast AP

Atria, Purkinje fibreventricle

SA/AV nodes

Class 1 Anti-arrhythmics

CLASS 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.Quinidine ProcainamideDysopyramide

Class 1B e.g.Lidocaine PhenytoinMexiletine

Class 1C e.g.EncainideFlecainide(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: Lidocaine Direct 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.

Use dependencelidocaine

lidocaine

Class 1B Typical example: Lidocaine

In 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 stabilizeroften used as an adjunct to other therapies.BUT contraindicated in:

•   acute heart failure •  asthma (why?)•   arrhythmias with A-V block

Note: Adrenaline can cause arrhythmias through effects on the pacemaker potential and delayed after-depolarizations. Antagonism of the ß1-receptors prevents this.

SA/AV node

CLASS III Anti-arrhythmics "Prolong APD and ERP, no effect on rise time “

• Action on phase 3 of AP waveform• Delays repolarization, lengthens APD• Action on IKR,IKS current K channel sub-types

Potassium channel blockers

Can have “reverse use-dependence” (with the exceptionof amiodarone)

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 effects

Example: Sotalol. ß-Blocker and Class III Anti-arrhythmic….prolongs APDUsed for severe VT and VF especially if patients can’ttolerate amiodarone

Can lengthen AP duration too much!

Drugs: Long QT and TdP

Drugs: LQT and TdP

Drugs that prolong QT..

Drugs that prolong QT..cont

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 by hepatic CYP3A4 activity (cytochrome P450-3A4).If CYP3A4 activity is inhibited then terfenadine levels rise. Terfenadine is a very good inhibitor of IKr (HERG) current in the heart leading to TdP. Many antifungal and antibiotics inhibit CYP3A4.

The active metabolite fexofenadine is now marketed as Allegra

CLASS 4 Anti-arrhythmicsEg.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 vascularCalcium channels

Other clinically important anti-arrhythmics.

Adenosine      occurs naturally

      electrophysiological effects like ACh decreases sinus rate; decreases A-V conduction• useful for supraventricular tachycardias • also anti-ischemic

      short t1/2

Action of adenosine is through

The A1 receptor directly coupled

To the Potassium channel GIRK

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.)

Glycosides and afterdepolarizations