Cardiovascular: Pharmacology - Antiarrhythmics Flashcards
Describe the Vaughan-Williams classification of antiarrhythmics
Class I: Na+ channel blockers
Class II: B blockers
Class III: prolong action potential
Class IV: CCBs
Name four other antiarrhythmic drugs not covered by the Vaughan-Williams classification
- Ivabradine
- Adenosine
- Mg2+
- K+
Describe the subclasses of class I antiarrhythmics
IA: intermediate dissocation, mixed properties of IB/IC, class III effects
IB: fast dissociation
IC: slow dissociation
Give four examples of class IA antiarrhythmics
Procainamide
Quinidine
Disopyramide
TCAs
Give three examples of class IB antiarrhythmics
Lidocaine
Phenytoin
Mexiletine
Give three examples of class IC antiarrhythmics
Flecainide
Propafenone
Moricizine
Give five examples of class III antiarrhythmics
- Amiodarone
- Sotalol
- Dronedarone
- Dofetilide
- Ibutilide
Give two examples of class IV antiarrhythmics
- Verapamil
- Diltiazem
Describe the difference between class IA, IB and IC antiarrhythmics in terms of their effect on AP and their speed of dissociation from the Na+ channel
IA: prolong AP duration, dissociate from Na+ channel with intermediate kinetics
IB: may shorten AP duration, binds to open INa channel and dissociates rapidly (in the course of a normal beat), selectively binds to refractory INa (such as in ischaemia) and has little effect on normal cardiac tissue
IC: minimal effect on AP duration, dissociates from INa with slow kinetics, generally decreases excitability
What is the effect of class IA antiarrhythmics on the ECG?
Prolongs QRS and QT interval
What is the effect of class IB antiarrhythmics on the ECG?
Little effect on ECG (may decrease QT)
What is the effect of class IC antiarrhythmics on the ECG?
Prolongs QRS
Outline the possible adverse effects of class IA, IB and IC antiarrhythmics
IA: proarrhythmic (TdP), hypotension, decreased LV function
IB: proarrhythmic (decreased QT -> VT), risk of re-entry with lidocaine
IC: proarrhythmic (TdP), decreased LV function
Describe the pharmacokinetics of lidocaine
Absorption: high first-pass metabolism (3% oral bioavailability), t1/2 = 1-2hrs
Distribution: decreased Vd in HF, increased Vd in liver disease (due to reduced plasma clearance)
Metabolism: largely hepatic
Excretion: decreased clearance in HF and liver disease (also with drugs reduce hepatic blood flow e.g. propranolol)
Describe the pharmacodynamics of lidocaine
Class IB antiarrhythmic: blocks INa with rapid kinetics, more effect on cells with long AP (e.g. Purkinje, ventricular) due to preferential inactivated INa blocking
What are the clinical applications of lidocaine?
Ventricular arrhythmias, especially if associated with MI (more effective on ischaemic tissue)
What is the effect of lidocaine toxicity?
May cause hypotension in large doses, especially in setting of HF, due to decreased contractility
What is one of the least cardiotoxic Na+ channel blockers?
Lidocaine
Describe the pharmacodynamics of flecainide
Class IC antiarrhythmic: blocks Na+ channel with slow kinetics, also blocks IK
Results in: decreased pacemaker activity ++, increased refractory period of depolarised cells, Na+ channel blockade ++ on depolarised cells
What are the clinical applications of flecainide?
Useful in supraventricular arrhythmias in patients with structurally normal hearts
Effective in suppressing PVCs but may cause severe exacerbation in patients with pre-existing ventricular tachyarrhythmias and those with previous Mi and ventricular ectopy
Describe the pharmacokinetics of flecainide
Absorption: good bioavailability, t1/2 = 20hrs
Elimination: hepatic and renal
Lidocaine dosing
Bolus 150-200mg over 15mins (decreased dose in HF)
Maintenance 2-4mg/min (decreased rate in HF and liver disease)
Flecainide dosing
100-200mg/day
Draw a ventricular action potential and show the effects of class IA, IB and 1C antiarrhythmics on it
Draw a pacemaker potential and show the effects of sympathetic stimulation and B-blockers (/parasympathetic stimulation) on it
Describe the pharmacodynamics of class II antiarrhythmics
Sympatholytic, decreases B-adrenergic activity in the heart:
1. Decreases repolarising K+ and Cl- currents
2. Decreases slow-inward Ca2+ current and Ca2+ storage in SR (which may contribute to delayed after-depolarisations)
3. Decreases pacemaker potential current
4. Increases serum K+
What is the clinical application of class II antiarrhythmics?
Useful in arrhythmias due to sympathetic over-activation (e.g. post MI)
Describe the pharmacodynamics of sotalol
Class II antiarrhythmic with class III properties (inhibits INa and IK)
Describe the effects of specific sotalol isomers
All B-adrenergic activity in L-sotalol; both D- and L-sotalol prolong AP
What is the clinical application of sotalol?
Used for life-threatening ventricular arrhythmias and for maintenance of SR in patients with AF
Describe the pharmacokinetics of sotalol
Absorption: oral bioavailability nearly 100%
Metabolism: not metabolised in liver, not bound to plasma proteins, t1/2 = 12hrs
Excretion: predominantly renal in unchanged form
Describe four adverse effects of sotalol
- Dose-dependent risk of TdP
- Reduced LVEF in patients with HF
- QT prolongation
- Contraindicated in asthma
Describe the concept of reverse-use dependence in class III antiarrhythmics
AP prolongation is least marked at fast rates, most marked at slow rates (contributes to increased risk of TdP)
Describe the pharmacodynamics of class III antiarrhythmics
Prolong AP, usually by blocking K+ channels or enhancing inward current
Causes increased refractory period
Draw a ventricular action potential and the effect of class III antiarrhythmics on it
Draw the effect of all classes of antiarrhythmics on cardiac action potentials
Describe the pharmacodynamics of amiodarone
Class III antiarrhythmic: prolongs AP by blocking IKr (and IKs during chronic administration)
Also has class I activity (blocks inactivated Na+ channels), and weak class II and IV activity, some a-blockade (causes hypotension, vasodilation)
Overall effect: decreased HR and AV node conduction, decreased automaticity in Purkinje fibres
Does amiodarone exhibit reverse-use dependence?
No, blocks AP uniformly over range of HR
What is the clinical application of amiodarone?
Used for serious ventricular arrhythmias (treats and prevents recurrence of VT/VF) and for supraventricular arrhythmias (e.g. AF)
Describe the pharmacokinetics of amiodarone
Absorption: oral bioavailability 35-65%
Distribution: very large Vd, strongly protein bound, t1/2 = 3-10 days (rapid component, ~50% of drug) and several weeks (slow component), effects maintained 1-3 months post discontinuation with measurable tissue levels for up to 1yr
Metabolism: hepatic metabolism via CYP3A4 (inhibitors decrease level, inducers increase levels; amiodarone itself is a P450 inhibitor)
Elimination: via hepatobiliary system
Describe amiodarone dosing
Loading: 10g total in 0.8-1.2mg daily doses
Maintenance: 200-400mg daily (100-200mg daily used in AF)
List seven features of amiodarone toxicity
- Bradycardia and HB if pre-existing SA/AV node disease (especially with IV loading)
- Hypotension (especially with IV loading)
- Dose-related pulmonary fibrosis
- Hepatitis, abnormal LFTs
- Photodermatitis: grey-blue skin discolouration with sun exposure
- Optic neuritis
- Hypo-/hyper-thyroidism (due to inhibition of T4 -> T3 and inorganic iodine loading)
Describe the pharmacodynamics of class IV antiarrhythmics. What channels do they inhibit?
Blockade of cardiac Ca2+ current to slow conduction in regions where AP upstroke is Ca2+-dependent (i.e. SA and AV nodes)
Inhibit L-type Ca2+ channels, inhibiting slow Ca2+ influx to cause:
1. Decreased SA/AV node conduction
2. Negative inotropy
3. Decreased ectopy due to reduced Ca2+ release from SR
4. Decreased after-depolarisations
Which CCBs are used as class IV antiarrhythmics?
Verapamil and diltiazem
(Dihydropyridines may precipitate arrhythmias)
What is the clinical application of class IV antiarrhythmics?
Used in supraventricular arrhythmias
What is one adverse effect of class IV antiarrhythmics?
Hypotension
Describe the pharmacodynamics of adenosine
Endogenous nucleoside, binds to GPCR and activates cAMP
Activation of inward rectifier K+ current
Produces marked hyperpolarisation
When given as bolus, inhibits AV nodal conduction and increases AV nodal refractory period (less effect on SA)
Describe the pharmacokinetics of adenosine
t1/2 <10secs
Less effective in presenc eof adenosine receptor blockers (e.g. caffeine, theophylline)
List three adverse effects of adenosine
- Flushing
- Shortness of breath
- Induction of high-grade AVB (short-lived) or AF
Outline the pharmacodynamics of ivabradine
Selective blocker of If (funny current) in SA node: decreased HR without decreased inotropy or decreased intracardiac conduction
What are the clinical applications of ivabradine?
Potential uses in HF, angina, and inappropriate sinus tachycardia
Describe the pharmacodynamics of magnesium as an antiarrhythmic
Unknown
What are the antiarrhythmic indications for magnesium?
Used in digoxin-induced arrhythmics if hypoMg present
Also in TdP with normoMg
Outline the AF rhythm control algorithm in the presence of absence of structural heart disease
Structural heart disease: sotalol if CAD, amiodarone if HF or HTN with LVH, second line catheter ablation
No or minimal heart disease: paroxysmal either flecainide/sotalol or catheter ablation, persistent flecainide/sotalol with second-line catheter ablation, amiodarone third-line in paroxysmal and second- or third-line in persistent
What are the two broad mechanisms of cardiac arrhythmias?
- Disturbances of impulse formation
- Disturbances of impulse conduction
What are five mechanisms of disturbed impulse formation?
- Neural effects (sympathetic/parasympathetic)
- Genetic mutations altering pacemaker activity
- Accelerated pacemaker activity in cells with slow phase 4 depolarisation at normal conditions (e.g. Purkinje cells)
- Early afterdepolarisations
- Delayed afterdepolarisations
Give two examples of disturbances of impulse conduction
- AV node conduction disturbance (e.g. HB)
- Re-entry
Explain the difference between early and delayed afterdepolarisations
Early: during phase 3, normally triggered by factor which prolong AP (e.g. prolonged QT)
Delayed: during phase 4 (especially at increased HRs), triggers by excess Ca2+ accumulation (e.g. in digoxin toxicity, catecholamine excess, MI)
Describe re-entry arrhythmias
Impulse re-enters and excites areas of the heart more than once
May be unidirectional block which prevents anterograde conduction but permits retrograde
List three causes of unidirectional block in re-entry arrhythmias
- Ischaemia
- Decreased Na+ channel activity in atrial/ventricular/Purkinje cells
- Decreased Ca2+ channel activity in AV nodes