antiarrhythmic drugs
DESCRIPTION
Antiarrhythmic drugs. Tuan norizan bt. Tuan mahmud Pakar anaestesiology , hsnz. LECTURE’S OUTLINE:. Electrophysiology of the heart Arrhythmia: definition, mechanisms, types Drugs :class I, II, III, IV, others Guide to treat some types of arrhythmia. Physiology of the normal heart. - PowerPoint PPT PresentationTRANSCRIPT
Electrophysiology of the heart
Arrhythmia: definition, mechanisms, types
Drugs :class I, II, III, IV, others
Guide to treat some types of arrhythmia
Normal conduction pathway:
1- SA node generates action
potential and delivers it to the atria and the AV
node
2- The AV node delivers the impulse to
purkinje fibers
3- purkinje fibers conduct the
impulse to the ventricles
Action potential of the heart:
In the atria, and ventricles the AP
curve consists of 5 phases
In the SA node , AV node and purkinje
AP curve consists of 3 phases
Non-pacemaker action potential
Phase 0: fast upstroke
Due to Na+ influx
Phase 3: repolarizati
onDue to K+
efflux
Phase 4: resting
membrane potential
Phase 2: plateu
Due to Ca++ influx
Phase 1: partial repolarizationDue to rapid efflux of K+
N.B. The slope of phase 0 = conduction velocityAlso the peak of phase 0 = Vmax
Pacemaker Action Potential
Phase 4: pacemaker potential
Na influx and K efflux and Ca
influx until the cell reaches
threshold and then turns into
phase 0
Phase 0: upstroke:
Due to Ca++ influx
Phase 3: repolarization:
Due to K+ efflux
Pacemaker cells (automatic cells) have unstable membrane potential so they can generate AP spontaneously
Effective refractory period (ERP)
It is also called absolute refractory period (ARP) :
•In this period the cell can’t be excited
•Takes place between phase 0 and 3
If the arrhythmia arises from
the ventricles it is called ventricular arrhythmia
If the arrhythmia arises from
atria, SA node, or AV node it is
called supraventricular arrhythmia
Delayed afterdepolarizat
ion
Early afterdepolarizat
ion
↑AP from SA node
AP arises from sites other than SA node
Refers to the accelerated generation of an action potential by either normal pacemaker tissue (enhanced normal automaticity) or by abnormal tissue within the myocardium (abnormal automaticity).
The discharge rate of normal or abnormal pacemakers may be accelerated by drugs, various forms of cardiac disease, reduction in extracellular potassium, or alterations of autonomic nervous system tone
AED –AP occurs during repolarization
CausesCongenital defective of K
channelProlong QT syndrome
Abn Na Channel- fast recovery to resting state
K channel blockers drugHypokalemia eg: use of
diureticBradycardia prolong
Action potential duration
DAD –AP occurs once repolarization complete
caused by intracellular Ca / Na overloadAdrenergic stimulation
(Ca & Na overload)Digitalis (- Na K APTase,
red Na effux, >NA intra cellular, + Na Ca exchanger ,
Miocardia Ischaemia/ infaction( reduce O2, reduce ATP production, reduce Na K ATPase activity
arrhythmias that arise as a result of afterdepolarizations (abnormal depolarizations that interrupt phase 2, phase 3, or phase 4 ) which on depends of the prior impulse (or series of impulses)
This is when the impulse is not
conducted from the atria to the
ventricles
1-This pathway is blocked
2-The impulse from this pathway
travels in a retrograde
fashion (backward)
3-So the cells here will be
reexcited (first by the original
pathway and the other from the
retrograde)
Reexcitation of cardiac tissue by return of the same cardiac impulse using a circuitous pathway
Due to imbalance of conduction and refractories
Mech of PVCVT and VFSVT,AF,flutter
Here is an accessory
pathway in the heart called
Bundle of Kent
•Present only in small populations
•Lead to reexcitation Wolf-Parkinson-White Syndrome
(WPW)
Abnormal anatomic conduction
In case of abnormal generation:
Decrease of phase 4 slope (in pacemaker cells)
Before drug
after
phase4
Raises the threshold
In case of abnormal conduction:
↓conduction velocity
(remember phase 0)
↑ERP(so the cell won’t be
reexcited again)
Tachydysrhythmias
Regular Irregular
Narrow complex Wide complex Narrow complex Wide complex
Sinus TachycardiaAtrial Tachycardia
Atrial FlutterAVNRT/AVRT
Ventricular tachycardiaPacer-mediated
tachycardiaSVT with pre-existing BBB
SVT with rate-dependent BBB
MATAtrial Fibrillation
Atrial Flutter with variable block
Torsade des PointesVentricular fibrillation
The ultimate goal of antiarrhythmic drug therapy:
Restore normal sinus rhythm and conduction Prevent more serious and possibly lethal
arrhythmias from occurring. Antiarrhythmic drugs are used to: decrease conduction velocity change the duration of the effective
refractory period (ERP) suppress abnormal automaticity
classmechanismactionnotes
INa+ channel
blockerChange the slope of
phase 0
Can abolish tachyarrhythmia
caused by reentry circuit
II β blocker↓heart rate and
conduction velocity
Can indirectly alter K and Ca conductance
III K+ channel blocker
1. ↑action potential duration (APD) or
effective refractory period
(ERP).2. Delay
repolarization.
Inhibit reentry tachycardia
IVCa++ channel
blocker
Slowing the rate of rise in phase 4 of SA node & conduction
velocity
↓conduction velocity in SA and
AV node
•Most antiarrhythmic drugs are pro-arrhythmic (promote arrhythmia)•They are classified according to Vaughan William into four classes
according to their effects on the cardiac action potential
They ↓ conduction velocity in non-nodal tissues (atria, ventricles, and
purkinje fibers)They act on open Na+ channels or inactivated only
Have moderate K+ channel blockade
So they are used when many Na+
channels are opened or
inactivated (in tachycardia only) because in normal
rhythm the channels will be at rest state so the drugs won’t
work
Slowing of the rate of rise in phase 0 ↓conduction velocity
↓of Vmax of the cardiac action potential
prolong muscle action potential & ventricular (ERP)
↓ the slope of Phase 4 spontaneous depolarization (SA node) Decreased pacemaker activity
They make the slope more horizontal
Intermidiate interection with sodium channel blocker Pharmacokinetics:
Supraventricular and ventricular arrhythmias Quinidine –prevent recurrent supraventricular
tachydysrhythmias & suppress ventricular premature contraction
Oral quinidine/procainamide are used with class III drugs in refractory ventricular tachycardia patients with implantable defibrillator
IV procainamide used for hemodynamically stable ventricular
tachycardia for acute conversion of atrial fibrillation including
Wolff-Parkinson-White Syndrome (WPWS)
Systemic lupus erythromatosus (SLE)-like symptoms: arthralgia,
fever, pleural-pericardial inflammation.
Symptoms are dose and time dependent
Common in patients with slow hepatic acetylation
Notes:Torsades de pointes: twisting of the point .
Type of tachycardia that gives special characteristics on ECG
At large doses of quinidine cinchonism occurs:blurred vision, tinnitus, headache, psychosis and gastrointestinal
upsetQuinidine has anti vagal action accelerate AVN
conduction Digoxin is administered before quinidine to prevent the conversion of atrial fibrillation or flutter into
paradoxical ventricular tachycardia
Adverse effect of Disopyramide --Negetive inotropic effect , CI in Cardiac failure or AV block
-Urinary retension,dry mouth,blurred vision & precipitated glaucoma (anticholinergic activity)
- Sinus Node depression& Prolong QTVentricular reentry arrythmia, VF, TDP
They shorten Phase 3 repolarization
↓ the duration of the cardiac action potential
Suppress arrhythmias caused by abnormal automaticity
Show rapid association & dissociation (weak effect) with Na+ channels with appreciable degree of use-dependence
Min change on conduction velocity
Lidocaine Used IV because of
extensive 1st pass metabolism
Clearence is related to hepatic blood flow, liver fx,microsomal activity-prolong in liver dis, heart failure, elderly
Propanolol , cimetidine, halothane dec hepatic clearence of lignocaine
Mexiletine
Oral analogs of lidocaine
Used for chronic treatment of ventricular arrhythmias associated with previous myocardial infarction
UsesThey are used in the treatment of ventricular arrhythmias arising during myocardial ischemia or due to digoxin toxicityThey have little effect on atrial or AV junction arrhythmias (because they have min effect on conduction velocity)
Adverse effects:1 -neurological effects
2 -negative inotropic activity
26
24
22
20
18
16
14
12
10
8
6
4
2
0
Death
Ventricular Arrest
Cardiac ArrhythmiaRespiratory arrest
Myocardial depression
Plasma lidocaine concentration µg/ml
Coma
Loss of conciousness
Convulsion
Muscle twitching
Visual disturbances
Lightheadness, tinnitus, circumoral & tongue numbness
Positive inotropy, anticonvulsant, antiarrythmic
CNS excitation
Markedly slow Phase 0 fast depolarization
Markedly slow conduction in the myocardial tissue
They possess slow rate of association and dissociation (strong effect) with sodium channels
Have only minor effects on the duration of action potential and refractoriness
Reduce automaticity by increasing the threshold potential rather than decreasing the slope of Phase 4 spontaneous depolarization.
Clinical use Refractory ventricular
arrhythmias. particularly potent
suppressant of premature ventricular contractions (beats)
Dosage :Orally :100 – 200 mg bdIV :2 mg/kg up to 150
mg over 10-30 mins Infusion : 1.5 mg/kg/h for 1 hour,
Then 0.1 – 0.25 mg/kg/hTherapeutic plasma
con. : 0.2-1.0 ug/ml
PharmacokineticsRapid and complete
absorbed after oral: bioavailability-90%
40-50% protein bindingVd: 5-10 L/kg
Metabolized in liver25% excreted unchanged
by the kidneysElimination half life: 7-15
hElimination decrease in ;
CCF , renal failure
Drugs interactionFlecainide increase the
plasma concentrations of digoxin and propanolol
Toxicity and Cautions for Class IC Drugs: Potentially serious proarrhythmogenic effect
causing: severe worsening of a preexisting arrhythmia
(ventricular arrhythmia aggravated in 5-12 % patient)
In patients with frequent premature ventricular contraction (PVC) following MI, flecainide increased mortality compared to placebo.
CNS effect comman- diziness, visual disturbance, GIT upset
Notice: Class 1C drugs are particularly of low safety and have shown even increase mortality when used
chronically after MI
Compare between class IA, IB, and IC drugs as regards effect on Na+ channel
& ERP
Sodium channel blockade: IC > IA > IB
Increasing the ERP:IA>IC>IB (lowered)
Because of K+
blockade
Mechanism of action Negative inotropic
and chronotropic action.
Prolong AV conduction (delay)- prolong PR interval
Diminish phase 4 depolarization suppressing automaticity(of ectopic focus)
Clinical UsesTreatment of increased
sympathetic activity-induced arrhythmias such as stress- and exercise-induced arrhythmias
Atrial flutter and fibrillation.
AV nodal tachycardia.
Reduce mortality in post-myocardial infarction patients
Protection against sudden cardiac death
Clinical useShort term
management of tachycardia and hypertension in peri-operative period, acute SVT
No intrinsic sympathomimetic activity or membrane stabilizing properties
Adverse effectCardiac
precipitate heart failure
Non cardiac act B2-
adrenoreceptor antagonism at high dose – caution in asthmatics
Irritant to veins and extravasations - tissue necrosis
PharmacokineticProtein bound – 60%Rapid metabolized by red blood cell esterase to inactive acid metabolism and methyl alcoholHalf-life 10 minute
Oral dose: 10 to 80mg every 6-8
hr ( Chronic suppression
of ventricular dysrhythmia)
IV: 1 mg per minute, total dose3 to 6mg
(emergency suppression of cardiac dysrythmia)
Adverse effectsBradycardia,hypotension,
myocardial suppression and bronchospasm, acccentuate CCF
cross placenta readily. Fetal bradycardia, hypoglycaemia, hyperbilirubinaemia and intrauterine growth retardation (IUGR) are concerns.
Most reports have not shown significant adverse fetal effects but beta-blockers are probably best avoided in known IUGR
Propranolol was proved to reduce
the incidence of sudden arrhythmatic
death & reinfact after myocardial infarction
Prolongation of phase 3 repolarization without altering phase 0 upstroke or the resting membrane potential
prolong both the duration of the action potential and ERP
Clinical Uses: Wide spectrum activity against refractory
supraventricular and ventricular tachyarrhythmia
Pulseless ventricular tachycardia and fibrillation resistant to defibrillation
Effective for suppression of tachyarrhythmia a/w WPWS
Sotalol (Sotacor) non selective B adrenergic blockade
prolongs the duration of action potential and refractoriness in all cardiac tissues (by action of K+ blockade) – class 111 action
suppresses Phase 4 spontaneous depolarization possibly producing severe sinus bradycardia (by β blockade action)
β-adrenergic blockade combined with prolonged action potential duration may be of special efficacy in prevention of sustained ventricular tachycardia
Most dangerous S/ E: the polymorphic torsades de pointes ventricular tachycardia because
it increases ERP, prolong QT interval
Ibutilide Used in atrial fibrillation or flutter Only drug in class three that possess pure K+ blockade
Slow repolarization by enhance influx Na, blocked Prolong cardiac action potensials K channel
IV administration May lead to torsade de pointes
A Benzoflurance derivative, resembles thyrosineAmiodarone is a drug of multiple actions ,complex comprising
class I, II, III, and IV actionsDominant effect: Prolongation of action potential duration and
refractorinessIt slows cardiac conduction, works as Ca2+ channel blocker,
and as a weak β-adrenergic blocker
Dose and administrationVF/VT unresponsive to CPR, shock and vasopressor
IV: 300 mg (5mg/kg) bolus
Life threatening arrhythmiasMax dose: 2.2 g IV over 24HRapid Infusion 150 mg over 10 minutes , Slow infusion: 360 mg
over 6H, Maintenance Infusion: 540 mg over 18HTherapeutic blood level: 1.0 – 3.5 mcg/ml
PharmacokineticsPoorly absorbed from gut,oral bioav. 50-70%Highly protein-bound >95%Vd 2-70 l/kg
Elimination half-life 20-100 days
Hepatic metabolism produces desmethylamiodarone – antiarrhythmic activity
Not removed by hemodialysis
Drug interaction effect of other highly protein bound drugs
(phenytoin, warfarin) are increase – dose should adjust
Plasma level of digoxin may rise when amiodarone added
Toxicity Common with patient chronic treatment
Most common include GI intolerance, tremors, ataxia, dizziness, and hyper-or hypothyrodism (2-4 %)
Cardiac – bradycardia and hypotension. Prolonged QT interval (inc ventricular tachyarrrythmia including Torsade de points)
Corneal microdeposits may be accompanied with disturbed night vision
Others: liver toxicity, photosensitivity & rash (10 %) , gray facial discoloration, neuropathy, prox muscle weakness, and weight loss
The most dangerous side effect is pulmonary fibrosis which occurs in 2-5% of the patients
can be irreversible and life threatening -unusual at doses used for atrial fibrillation (200 mg/day)
10% fatal, most reversible
Calcium channel blockers decrease inward Ca2+ currents resulting in a decrease of phase 4 spontaneous depolarization (SA node)
They slow conductance in Ca2+ current-dependent tissues like AV node.
Examples: verapamil & diltiazemBecause they act on the heart
only and not on blood vessels.
Dihydropyridine family are not used because they only act on blood vessels
Prevents influx of Ca through slow (L) channel in SA and AV node – reduce their automaticity
They prolong ERP of AV node ↓conduction of impulses from the atria to the ventricles
Coronary artery dilatation
Clinical Uses More effective in treatment of atrial than ventricular arrhythmias.Treatment of supra-ventricular tachycardia preventing the occurrence of ventricular arrhythmiasTreatment of atrial flutter and fibrillation
Dose5 – 10 mg IV bolus over 1-3 min
Infusion 5 mcg/kg
Verapamil
PhamacokineticOrally and IV90% absorbed from gut,
oral bioav.25% d/t high first-pass metabolism
90% bound to plasma protein
Metabolized in liverExcreted in urineVd 3-5 l/kgElimination half-life 3-7
hrs
Adverse effectCardiac
SVT with WPW syndromeverapamil precipitate VT
Pt with poor LV functionprecipitate cardiac failure
With agent that slow AV conduction (digoxin,B-blocker, halothane) precipitate serious
bradycardia and AV blockIncrease serum level of
digoxinNon cardiac
cerebral artery dilatation, constipation
CI- Sick sinus syndrome. heart block, poor left
ventricular failure
AdenosineEndogenous nucleoside slows conduction of cardiac impulses
through the AVN and accessory pathways
usesEffective for stable narrow complex SVTEffective in terminating those due to
reentry involving AV node or sinus nodeRegular and monomorphic wide-complex Not effective in AF, flutter or VT
Mechanism of actionIts stimulates cardiac
adenosine 1 receptors to increase K+ currents
shorten the action potential duration
hyperpolarize cardiac cell membranes.
In addition, Adenosine decrease cAMP concentration
PhamacokineticIts short-lived cardiac
effectsElimination half
time : 10 seconds by carrier-mediated cellular uptake
Dosage IV : 6mg iv rapid
bolus (over 1-3 second followed by NS bolus) , followed by a dose of 12mg if necessary
Drug interactionInhibit by
theophyllinePotentiated by
adenosine uptake inhibitors such as dipyridamole
Side effectsFacial flushing ,
Headache
Dyspnea, Chest discomfort
NauseaTransient
atrioventricular heart block, asystole
Rare – bronchospasm
Pharmacologic effects of adenosine are antagonized by methyxanthines (theophylline, caffeine) and potentiated by dipyridamole
Contraindication 2nd or 3rd degree heart
block & Sick sinus syndrome
Mode of actionCo-factor for membrane
enzyme Na+/K+ ATPaseLack of magnesium may
lead to intracellular K+ depletion
Slow the conduction trough AV node and prolong the refractory period in atria & ventricles– similar class 111
Clinical useTorsade de pointesVentricular arrhythmias
ass with digitalis toxicityMultifocal atrial
tachycardia
Dose: 1-2 g (2-4 ml of
50% solution) dilute in 50 ml D5 over 1h ( poorly absorbed from gut)
Mg is excreted by kidneys and accumulate in renal failure
Adverse effect Hypotension
Mode of actionDirect –
bind and inhibit cardiac Na+/K+ ATPase increase intracellular Na+ and decrease intracellular K+
Raised intracellular Na+ increased exchanged with extracellular Ca2+ resulting increase availability of intracellular Ca2+ positive inotopic effect, increasing excitability and force of contraction
Indirect- release of Ach at cardiac muscarinic receptors – slow
conduction and prolong refractory period in AV node and bundle of HIS
Clinical useTreatment of atrial
fibrilation or flutter
DoseLoading dose 1 – 1.5
mg, divided dose over 24h
Maintenance dose 125 – 500 mcg/day
Therapeutic range 1-2 mcg/l
Adverse effectCardiac
PVC, bigemini, all form of AV block
ECG – prolonged PR interval, ST segment depression, T wave flattening and short QT interval
Non cardiacAnorexia, nausea and
vomiting, diarrhoe and lethargy,
visual disturbance, headache and gynecosmatia
Toxicity – plasma conc >2.5 mcg/l
Treatment of digoxin toxicityStop digoxin adm. Gastric lavage, actvated
charchoalCorrect precipitating factor – K+SVT – propanololAV blockade – pacing, atropine,
isoprenalineVentricular arrhythmias – phenytoin,
lignocaine, pacingDigoxin – specific Fab a/body fragments
classECG QTConduction velocity
Refractory period
IA++↓↑
IB0no↓
IC+↓no
II0↓In SAN and AVN↑ in SAN and AVN
III++No↑
IV0↓ in SAN and AVN↑ in SAN and AVN
1st: Reduce thrombus formation by using anticoagulant warfarin
2nd: Prevent the arrhythmia from converting to ventricular arrhythmia:First choice: class II drugs:•After MI or surgery•Avoid in case of heart failure
Second choice: class IV
digoxin•Only in heart failure of left ventricular dysfunction
3rd: Conversion of the arrhythmia into normal sinus rhythm:Class III:IV ibutilide, IV/oral amiodarone, or oral sotalol
Class IA: ( no longer recommended except vagally mediated AF coz More effective drug available , extra cardiac side effect & proarrythmia effect)Oral quinidine + digoxin (or any drug from the 2nd step)
Class IC:Oral propaphenone or IV/oral flecainide
Use direct current in case of unstable
hemodynamic patient
Address precipitating factors :
hyperthyroidism, heart failure & etc