Antiarrhythmics Pharmacology and PKPD

general mechanism of antiarrhythmic agents?

aim of therapy is to reduce ectopic pacemaker activity and modify conduction or refractoriness via sodium channel blockade, blockade of sympathetic autonomic effects of the heart, prolongation of the effective refractory period (often potassium channel blockade) and/or calcium channel blockade

properties of antiarrhythmics

decrease/suppress the automaticity of ectopic pacemakers and abnormal conduction in depolarized cells while minimally affecting normal electrical activity such as the SA node.

what does use dependence or state dependence mean in relation to antiarrhthmics

selective inhibition of tachycardic myocytes, while minimizing impact on cells with normal activity

T/F: as doses of antiarrhythmics increase, they may depress conduction in normal tissues leading to drug-induced arrhythmias

True

what are sodium channel blockers?

membrane stabilizers (decrease excitability of cardiac tissue)

which drugs are moderate potency sodium channel blockers?

Disopyramide, quinidine, procainamide

which drugs are low potency sodium channel blockers?

Lidocaine and mexiletine

which drugs are high potency sodium channel blockers?

Flecainide and propafenone

how do beta blockers help arrhythmias

block sympathetic input (all beta-blockers!)

what are potassium channel blockers?

extend the refractory period

potassium channel blockade drugs?

sotalol, dofetilide, amiodarone, dronedarone, ibutilide

what are calcium channel blockers?

negative inotrope and chronotrope

calcium channel blockade drugs?

verapamil and diltiazem

what do all Class IA antiarrhythmics do?

slow upstroke of the action potential, slows conduction, and prolongs the PR interval or QRS duration by Na+ channel blockade

Which Class IA antiarrhythmic agent has the most cardiac antimuscarinic effects?

disopyramide

Since disopyramide is a negative inotrope what can it cause?

can cause or precipitate heart failure

which Class IA antiarrhythmic agent has modest antimuscarinic effects?

quinidine

which drug has some K+ channel blockade and can lead to Torsade de Pointes

quinidine

which Class IA antiarrhythmic agent has direct depressant actions on the SA and AV nodes

procainamide

which drug increases refractory period and can cause Torsades de Pointes

Procainamide!

How does Lidocaine work?

blocks both activated and inactivated Na+ channels with rapid kinetics - the inactivated state block = increased effect on ventricular cells more than atrial cells; making it only useful for ventricular arrhythmias

which drug has extensive first-pass hepatic metabolism so it can only be given IV

Lidocaine

what drug is the orally active congener of lidocaine

mexiletine

T/F: lidocaine moves slowly from the blood to the heart

False - onset of action is within a few minutes of a loading dose

what drug needs a continuous infusion initiated after a loading dose to maintain concentrations

Lidocaine

how long after initiating lidocaine is equilibrium established

0.5-1 hour

what is the loading dose of lidocaine

1-1.5 mg/kg

how is lidocaine primarily elimanted

via hepatic metabolism via CYP3A4

T/F: liver blood flow impacts clearance of lidocaine

True

therapeutic range for lidocaine

1.5-5 mcg/mL

side effects if the lidocaine serum concentration is > 3 mcg/mL?

can develop drowsiness, dizziness, paresthesia, or euphoria

side effects if the lidocaine serum concentration is > 5 mcg/mL?

muscle twitching, confusion, agitation, dysarthria, psychosis, seizures, and coma

half life of lidocaine

1-1.5 hours in normal adults, up to 5 or more hours in patients with renal failure

when can lidocaine serum concentrations be measured?

at ~3-5 half-lives

when do most patients obtain therapeutic levels of lidocaine

usually within ~6 hours of initiation unless significant liver disease

if a patient on lidocaine has an arrythmia appear and the serum concentration is at < 5 mcg/mL, what should we do

increase the dosage

if a patient on lidocaine has an arrythmia appear and the level is > 5 mcg/mL what should we do?

higher doses are unlikely to suppress the arrhythmia, and higher concentrations are more likely to lead to side effects

what is the reason for side effect if a side effect occurs in lidocaine patients and their serum level is < 3 mcg/mL

not sure b - just not usually the lidocaine

examples of Class IC antiarrhythmics

flecainide, propafenone

which antiarrhythmic class is the most potent sodium channel blocker?

Class IC

which drug is a potent sodium channel blocker and possesses some weak beta-blocking activity?

propafenone

what class antiarrhythmic are all beta-blockers?

Class II

T/F: efficacy of suppression of ventricular ectopic depolarization is lower for beta-blockers than sodium channel blockers

true

which subgroup of beta-blockers are the most effective for prevention and treatment of arrhythmias?

non-selective beta-blockers (ex: propranolol, nadolol)

what needs to be monitored on an ECG for patients taking Class III antiarrythmics?

the QT interval - if it elongates too far, it can cause Torsade de Pointes (TdP)

what is Torsade de Pointes?

a life-threatening arrythmia

which antiarrhythmics have reverse-use dependence?

Exhibited by most Class III antiarrythmics

what is reverse-use dependence

where action potential prolongation is least marked at fast rates (where it is desirable) and most marked at slow rate leading to increased risk of Torsades de Pointes

What does sotalol block?

it is a beta-blocker and potassium channel blocker

T/F: sotalol is a racemic mix and both the L and D versions do beta and K+ channel blockade

true

what does dofetilide block?

dose dependent blockade of potassium channels

Examples of Class III antiarrhythmics

sotalol, dofetilide, amiodarone, dronedarone, ibutilide

how does amiodarone work in the heart?

blocks sodium channels and decreases HR/Av node conduction

Which Class III antiarrhythmic does not exhibit reverse-use dependence

amiodarone

does amiodarone cause significant QT prolongation ?

yes - but low incidence of Torsades de Pointes

what does ibutilide block

May block sodium channels

what enzymes/proteins does amiodarone inhibit?

PGP, CYP2C9. CYP2D6, and CYP3A4

what enzymes/proteins is amiodarone a substrate for?

CYP3A4, PGP, CYP1A2, CYP2C19, CYP2D6, and CYP2C8

half-life of amiodarone

~50 days

what are class IV antiarrythmic agents?

non-DHP CCBs such as verapamil and diltiazem

how do Non-DHP CCBs work?

they block calcium channels which decreases AV nodal conduction time and also directly decreases SA rate, but reflex tachycardia may result from vasodilation.

T/F: non-DHP CCBs are negative inotropes?

trueeeee

what do you need to monitor on an ECG for Class I antiarrythmics

the QRS complex