antiarrhythmic drugs background of cardiac electrophysiology membrane potential of cardiac cells...
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Antiarrhythmic DrugsAntiarrhythmic DrugsBackground of Cardiac ElectrophysiologyMembrane potential of cardiac cellsFast response : resting potential, High -80 ~ -95mv(Atrial muscles the rate of rise of phase 0 is rapidVentricular muscles propagation will be rapidPurkinje fiber) Na+ influx, rapid depolarization
Slow response : resting potential, low -50~ -70mv
(sinus, atrioventri- slow depolarization, Ca 2+ influx
cular (AV) nodel action potential propagates slowly cells, impaired fastResponse cells)
Phase 0 : depolarizationPhase 1,2,3 : repolarizationPhase 4 : diastolic voltage time course0 ~ 3 : action potential duration APD
K+,Cl-
Channel currents
Pump
Exchanger
K+ Ca2+
Na+Na+Ca2+
100ms
Outside
0mV
Na+
intsideMembrance
-85mV
0
1 2
3
4
Fast response
1. Excitability: relationship between threshold potential and restingpotential level
2. Automaticity: 3. Conductivity: conductive rate is dependent on membrane r
esponsiveness Membrane responsiveness: relationship between Vmax
of phase 0 and membrane potential level4. Effective refractory period, ERP The time between phase 0 and sufficient recovery of so
dium channels in phase 3 to permit a propagated response to external stimulus is the “refractory period” .
二 Mechanisms of arrhythmias
1. Disturbances of impulse formation ( 冲动形成障碍 )
① The changes of normal autonomic mechanism
Change of pacemaker current (cell) of diastolic autonomic depolarization can cause autonomic alteration
such as : mental stress (tension)
drug toxicity
fever
excitation
② formation of abnormal autonomic mechanism
non-autonomic cell: atrial muscles ventricular muscles
autonomic cell resting potential : -60mv
abnormal autonomy repetitive impulse arrhythmias
2. triggered activity ( 触发活动 ) and Afterdepolarization (后除极)
A Early afterdepolarization ( EAD ,早后除极)
Occur in phase 2, 3 , low potassium, Ca 2+ inward
E.A. is secondary depolarization that occur before repolarization is complete. secondary depolarization commences at membrane potentials close to those present during the plateau of the action potential
B delayed afterdepolarization ( DAD, 迟后除极 )
Occur in phase 4, Ca 2+ overload in cell, Na + inward.
D.A. is a secondary depolarization that occurs early in diastole, that is, after full repolarization has been achieved.
3. Disturbances of impulse conduction (冲动传导障碍)
A causing partial and complete block
B reentry---fibrillation 心室纤颤 and flutter 心室扑动 tachycardia
extra beats ( extrasystoles)
formation unidirectional block of cardial tissue
of reentry circuiting tract
shortening the effective refractory period
Reentry circuit established
1 forward impulse obstructed and extinguished
2 decremental conduction (递减传导) and unidirectional block ( 单向阻滞 ) of antegrade (顺行) impulse
3 retrograde (逆行) impulse conducted across depressed region
4 reentry circuit established
Arrhythmia may be manifest as one or a few extra beats or as a sustained tachycardia
Reentry( 折返 ) : circus movement
one impulse reenters and excites areas of the heart more than once
Mechanism of the reentryMechanism of the reentry
正常心肌 单向传导阻滞
折返形成
4. Genetics/gene mutation
• Long Q-T SYNDROME, LQTS • 3 mutation genes:
SCN5A /chromosome 3: coding sodium channel in myocardia;
HERG/ chromosome 7: coding Ikr potassium channel (内向整流钾通道) ;
KVLQT1/ chromosome 11: coding Iks potassium channel (延迟整流钾通道) ;
5. Disturbances of of Potassium channels
Classification of AntiarrhytClassification of Antiarrhythmic Drugshmic Drugs
Antiarrhythmic agents are divided into FOUR classes Antiarrhythmic agents are divided into FOUR classes
Assignment to the respective classes is made on the bAssignment to the respective classes is made on the b
asis of drug-induced alterations in ion channel function asis of drug-induced alterations in ion channel function
and cardiac electrophysiologic properties and cardiac electrophysiologic properties
The classification, while helpful, is not absolute and ovThe classification, while helpful, is not absolute and ov
erlapping properties exist among the many drugs.erlapping properties exist among the many drugs.
• A. Antiarrhythmic drugs can depress Na + inward of non-autonomic cell in phase 4 or depress Ca 2+ inward of autonomic cell in phase 4 depress automaticity
• B. Antiarrhythmic drugs can accelerate K+ outward of phase 3, increase maximum diastolic potential (more negative ) increase voltage difference between maximum diastolic potential and threshold potential depress automaticity
Question: How about the conduction?
Classes of antiarrhythmic agents
1. sodium channel blocking drugs.
2. blockade of sympathetic autonomic effects in
the heart
3. prolongation of the ERP and APD
4. calcium channel blockade
Classification of Antiarrhythmic DrugsClassification of Antiarrhythmic Drugs
• Class Ia-Characteristics Meddle level sodium channel block , weak level potassi
um channel block , and weak level calcium channel block in high concentration– Slow the rate of rise of the membrane action potential (Phase 0; dV
/dt ) – Slow conduction velocity (PR; QRS) – Prolong refractoriness (QT)
• Examples - – Quinidine* – Procainamide – Disopyramide
Classification IClassification I :: sodium channel blocking drugs
Classification of Antiarrhythmic DrugsClassification of Antiarrhythmic Drugs
• Class Ib -Characteristics
Weak level sodium channel block , and potassium channel open– Limited effect on dV/dt of Phase 0 – Slight slowing of conduction velocity – No change or a decrease in refractory period
• Examples – Lidocaine*
– Tocainide
– Mexiletine
– Moricizine ?
Classification of Antiarrhythmic DrugsClassification of Antiarrhythmic Drugs
Class Ic- Characteristics
Strong level sodium channel block , and weak level calcium channel block– Marked slowing of conduction velocity (prolongs PR a
nd QRS) – No change in refractoriness or repolarization
• Examples – Flecainide*
– Propafenone (also Class II)
– Moricizine (also Class Ib)
– Encainide (discontinued)
Classification of Antiarrhythmic DrugsClassification of Antiarrhythmic Drugs
• Class II-Characteristics – Produce beta-adrenergic receptor blockade (p
rolongs PR; slows heart rate) – Decrease in refractory period duration (decrea
se in QT) • Examples
– Propranolol* – Acebutolol – Esmolol – Sotalol (also Class III)
Classification of Antiarrhythmic DrugsClassification of Antiarrhythmic Drugs
• Class III-Characteristics potassium channel block
– Prolong the action potential duration – Increase the refractory period (increase in the
QT) • Examples
– Amiodarone (also some Class Ia,II,III,&IV) – Bretylium – Sotalol (also Class II) – Ibutilide*
• Class IV-Characteristics
• Blockade of calcium entry via slow inward channel (prolong the PR interval) – Examples
• Verapamil • Diltiazem
Classification of Antiarrhythmic DrugsClassification of Antiarrhythmic Drugs
Other Miscellaneous AgentsOther Miscellaneous Agents
• Adenosine – Depresses sinus node automaticity – Depresses atrioventricular node conduction
• Uses – Acute termination of AV nodal tachycardia – Acute termination of AV nodal reentrant tachy
cardia
• Digitalis (Digoxin) – Prolongs atrioventricular nodal conduction time and in
creases functional refractory period - directly and indirectly (increase in vagal cholinergic tone)
– Slows sinus rate when ventricular function is impaired by virtue of its direct positive inotropic effect (withdrawal of sympathetic tone)
• Uses: – Atrial fibrillation or flutter - primarily to control the ventr
icular rate – AV nodal reentrant tachycardia
Other Miscellaneous AgentsOther Miscellaneous Agents
Class Ia Antiarrhythmic Agents Class Ia Antiarrhythmic Agents
• Quinidine (奎尼丁)• Procainamide (普鲁卡因胺)• Disopyramide (丙吡胺)
Quinidine Quinidine (奎尼丁)(奎尼丁)
Pharmacologic action
1 Quinidine depresses pacemaker rate, especially that
of ectopic pacemakers ( abnormal automaticity) depress automaticity of atrial, ventricular muscles, Purkinje, and sinoatrial nodes
Electrophysiologyinhibit Na+ inward , inhibit K+ outward , inhibit calcium inward in high concentration, depress slope phase 4 diastolic depolarization
2 Quinidine also lengthens the action potential duration
( APD) and effective refractory period (ERP)
depresses phase 3 K+ outward,
slow repolarization
lengthens the APD, and ERP
eliminates reentry impulses.
3 Negative conduction
blocks sodium channel, depresses Na + inward, reduces depolarization rate of phase 0, inhibits conduction responsiveness of membrane declines.
inhibits vagal activity, increases conduction of atrioventri-cular (AV) nodes, slow conduction of atrial muscles( reduce atrial bates) and increase the ventricular bates (ventricular fibrillation 心室纤颤 and flutter 心室扑动 )
• treating atrial fibrillation and flutter: combination with cardiac lycosides (digoxin), inhibiting conduction of AV node to prevent the ventricular bates.
• unidirectional block bidirectional block by abolished reentry impulse.
4 Electrocardiogram (ECG)
• QT interval is prolonged
• QRS wave is widened
Pharmacokinetics absorption : orally, rapid, in gastrointestinal tract
binding protein : 80%
bioavailability (F) :72%~87%
Vd : 2~3 L/kg
metabolism : in liver
excretion : 20% unchanged in the urine
t ½ 5~7 hours
urinary excretion is enhanced in acid urine
t ½ may congestive heart failure
be longer hepatic or renal diseases
older patients
Clinical uses
1 acute and chronic ventricular and supraventricular arrhythmias
2 most common indications: atrial fibrillation and flutter
combination with digoxin
3Qinidine can increase blood concentration and untoward reaction of digoxin.
• Toxicity• 1 Toxic dosage • depresses conduction of sinoatrial, atrial-ventri
cular nodes and Purkinje, cause conductive block of atrioventricle and intraventricle.
• severe toxication: automaticity of Purkinje can be enhanced,
• cause ventricular tachycardia and ventricular fibrillation (may be fatal) iv NaHCO3, K+ inward, K+ in blood is decreased, toxicity is decreased.
2 hypotention
Quinidine can block α- receptor, blood vessels relaxation ( vasodilation), inhibit myocardial concentrating force
3 thromboembolism
patient with atrial fibrillation easy to occur.
4 cinchonism 金鸡钠中毒headache, dizziness, tinnitus( 耳鸣) ,confused vision( 视力模糊 ), double vision( 复视 ), gastrointestinal discomfort,
fainting 晕厥 , psycholeptic episodes 精神失常 ( psychataxia mentation), confusion( 神志不清 )
5 others diarrhea, nausea and vomiting,
thrombocytopenia( 血小板减少症 ), bleeding
• 4 cinchonism 金鸡钠中毒• headache, dizziness, tinnitus( 耳鸣) ,confused
vision( 视力模糊 ),double vision( 复视 ),gastrointestinal discomfort,
• fainting 晕厥 , psycholeptic episodes 精神失常 • ( psychataxia mentation) ,confusion( 神志不清 )
• 5 others diarrhea , nausea and vomiting,
thrombocytopenia( 血小板减少症 ), bleeding
Classification of Antiarrhythmic DrugsClassification of Antiarrhythmic Drugs
• Class Ib -Characteristics
weak inhibit Na + inward
enhance K+ outward
depress slope phase 4 diastolic • Examples
– Lidocaine* (利多卡因)– Phenytoin sodium (苯妥英钠)
Lidocaine/Lidocaine/ 利多卡因利多卡因
• Action1. depressing automaticity (therapeutic dose)
lidocaine can suppress automaticity of Purkinje fibers, because of:
weak inhibit Na + inward
enhance K+ outward
depress slope phase 4 diastolic depolarization
2. duration of the action potential (APD) and effective refractory
period (ERP)
in Purkinje fibers and ventricular muscle: the drug can decrease (shorten) APD and ERP, but decreased APD > decreased ERP.
ERP is prolonged relatively
APD is shortened
Repolarization is rapid and complete, velocity of phase 0
depolarization can be quickened
3. conductivity in condition of ischemic Purkinje fibers of myocardial i
nfarction region the drug can inhibit Na+ inward decrease conduction prevent occur of reentry (from unidirecti
onal block changes to bidirectional block ) in condition of extracellular low K+ or partial depolariz
ation of myocardial tissues
the drug can enhance phase 3 K+ outward causing hyperpolarezition, improving conduction abolishing ventricular reentry (reducing unidirectional block)
0mV
-85mV
0
12
3
4
ADP
ERP
PharmacokineticsPharmacokinetics
1 very extensive first- pass hepatic metabolism ,only 3%
of orally administered lidocaine appears in plasma
the concentration in plasma is low
Thus, lidocaine must be given parenterally. im. iv.
2 protein binding rate is about 70%
3 t ½ is about 100 min
5~7h Css
Therapeutic useTherapeutic use
• 1 ventricular arrhythmias
ventricular tachycardia and fibrillation
• 2 ventricular arrhythmias caused by acute
myocardial infarction
• 3 open-heart surgery and digitalis toxication
Untoward effectsUntoward effects• 1 CNS lightheadedness 头晕 headache paresthesias 感觉异常 (often perioral 口周的 ) muscle twitching 抽搐 convulsion 惊厥 slurred speech 少言少语 hearing disturbances 听力失调 respiratory arrest 呼吸停止• 2 hypotension (partly by depressing myocardial contractility) sinoatrial nodal standstill 窦性停搏 impaired conduction• Contraindication ⅡⅢ---atrioventricular conduction block
Phenytoin sodiumPhenytoin sodium 苯妥英钠苯妥英钠
• The drug for the treatment of seizures (癫痫病发作)
• Clinical usefulness for ventricular arrhythmias , especially those associated with digitalis toxicity .
Action
1. Automaticity
Hastening k+ outward
Decreasing the slope of normal phase-4 depolarization in Purkinje fibers (increasing maximal diastolic potential.)
automaticity of abolishing delayed
Purkinje fibers afterdepolarization caused
by digitalis toxicity.
The drug substanitially decrease the APD.
Complete repolarization.
Level of membrane potential ( negtive potential)
Amplitude of action potential
Conduction velocity
Abolishing reentry.
2. APD and ERP in ventricular muscle and Purkinje fibers APD and ERP are shortened, but shortened APD >shortened EPR, so, EPR is rolonged relatively
3.Responsiveness and conduction.
Increasing phase-0 depolarization rate of atrial
muscle, atrioventricular node, Purkinje fibers of
digitalis toxicity.
Improving conduction.
• Therapeutic uses:
• 1.Ventricular arrhythmias.
• 2.Paroxysmal atrial flutter or fibrillation.
• 3.Supraventricular arrhythmias (tachycardia)
• 4.Ventricular arrhythmias caused by acute myocardial infarction, open-heart surgery and digitalis toxication
Classification of Antiarrhythmic DrugsClassification of Antiarrhythmic Drugs
Class Ic- Characteristics: Sodium channel blocker
– Marked slowing of conduction velocity (prolongs PR and QRS)
– No change in refractoriness or repolarization • Examples
– Flecainide* 氟尼卡 (also has potassium channel blocking)– Propafenone (also Class II) 普罗帕酮( also has functions of
-receptor inhibitor and calcium channel blocker )– Moricizine (also Class Ib) – Encainide (discontinued)
Propafenone (Propafenone ( 普罗帕酮普罗帕酮 ))
• Class Ic antiarrhythmic drug : strong sodium channel blok
• Possesses weak beta-adrenoceptor blocking properties
• Has weak calcium channel blocking properties (Negative inotropic action)
• Slows conduction in the atria, ventricles, AV node, His-Purkinje system and accessory pathways
• Slight increase in the ventricular refractory period
• Prolong ERP and APD, increasing ERP/APD
• Clinical Uses • Acute termination or long term suppression of ve
ntricular arrhythmias, particularly recurrent ventricular tachycardia
• In treatment of patients with life-threatening ventricular arrhythmias
• Immediate termination and long term prevention of supraventricular reentrant tachyarrhythmias involving the AV node or accessory pathways
• Long term suppression or refractory, symptomatic atrial fibrillation and flutter
• Dose – Initially 150 mg every 8 hours – May be increased at three to four day intervals to 225
mg every 8 hours
• Drug Interactions – Increases serum concentrations of digoxin, warfarin, a
nd propranolol
• Pharmacokinetics – Extensive first pass metabolism – Hepatic metabolism - (P450IID6, desbriso-quin hydro
xylation phenotype)
Class II Antiarrhythmic AgentsClass II Antiarrhythmic Agents
• Propranolol
• Esmolol
• Sotalol
• other beta-adrenoceptor antagonists
Beta - Adrenoceptor Blocking AgentsBeta - Adrenoceptor Blocking Agents
• Mechanism of Antiarrhythmic Action – Antiarrhythmic effects of Class II drugs are attributed t
o actions: • blockade of postsynaptic cardiac beta - adrenoceptors • membrane stabilizing action • Otherwise, as a sodium channel blocker to suppress diastolic a
utomatic depolarization in 4 phase (decreasing automaticity) and conductivity in 0 phase.
– The former, blockade of beta - adrenoceptors is the more important action, the latter may require higher concentrations than achieved with therapeutic doses
Cardiac Effects of beta - Adrenoceptor BlockerCardiac Effects of beta - Adrenoceptor Blocker
• Decreasing automaticity: as an adrenoceptor blocker to reduce the heart rate
• Decreasing conductivity: membrane stabilizing action (Lengthening of atrioventricular conduction time and minimal prolongation ventricular in refractoriness - (Sotalol prolongs the refractory period, Class III) )
• APD and ERP:
Clinical concentration: shorten APD and ERP;
Higher concentration: prolong APD and ERP;
Propranolol (Inderal™)Propranolol (Inderal™)
• Uses: – Major indications for propranolol as an antiarrhythmic
are: • atrial flutter • atrial fibrillation • AV nodal reentrant tachycardia • selected ventricular arrhythmias
– Prevents or terminates arrhythmias associated with excess cardiac sympathetic stimulation - e.g. exercise induced arrhythmias
Class III AntiarrhythmiaClass III AntiarrhythmiaProlong the Duration of Action Potential /potassium channel blocker (weak so
dium and calcium blocker)Drugs: • Bretylium 溴苄铵• Amiodarone 胺碘酮• Sotalol 索他洛尔• Ibutilide
• Uses: • Suppression of refractory, life-threatening, recurr
ent ventricular arrhythmias – ventricular tachycardia – ventricular fibrillation
• Prevents recurrences of atrial arrhythmias – atrial flutter – atrial fibrillation – AV nodal reentrant tachycardia
AmiodaroneAmiodarone 胺碘酮
Action and mechanism
• Decreasing aotumaticity:
• Decreasing conductivity:
• Prolong ERP:
Clinical Use
• supraventricular arrhythmias
Classification IV Cardiac Actions of the Classification IV Cardiac Actions of the Calcium Channel Blocking Agents/Calcium Calcium Channel Blocking Agents/Calcium
Channel BlockersChannel Blockers
Classification VClassification V :: Miscellaneous Antiarrhythmic AgentsMiscellaneous Antiarrhythmic Agents
• Adenosine
• Digoxin
Adenosine (Adenocard™)Adenosine (Adenocard™)
• Actions – Naturally occurring purine nucleoside – Degradation product of adenosine triphosphat
e (ATP) – Potent vasodilator of peripheral vessels and c
oronary arteries – Antiadrenergic actions – Negative chronotropic actions
Adenosine (Adenocard™)Adenosine (Adenocard™)
• Cardiac Electrophysiologic Actions – Depresses upstroke of action potential in N ce
lls of the AV node – Intravenous administration of adenosine
• suppresses sinus node automaticity • depresses AV nodal conduction velocity • increases AV nodal refractoriness
• Uses • First-line therapy for acute termination of AV nodal reentr
ant tachycardia and other supraventricular tachycardias in which the reentry loop involves the atrioventricular node
• When administered to patients in sinus rhythm, who have a history of paroxysmal supraventricular tachycardia, adenosine may reveal latent preexcitation by slowing or blocking conduction to the ventricles via the AV node, thereby uncovering the presence of a concealed bypass tract
• Dose • Intravenously, rapidly 6 mg over one to two
seconds • If the arrhythmia is not controlled within one to
two minutes, 12 mg may be given as a rapid intravenous injection
• The 12 mg dose may be repeated if needed • Do not give more than 12 mg as an individual
dose
Adenosine on Atrial MuscleAdenosine on Atrial Muscle• Control• After • Adenosine• Na+• Ca++• K+• Delayed Rectifier Channel opens during • repolarization resulting in potassium ion • efflux• ATP Dependent Potassium Channel opens • during repolarization resulting in an enhanced • potassium ion efflux that: • • terminates inward calcium ion movement
via the slow inward channel • decreases the atrial refractory period • increases atrial muscle conduction velocity
• Actions of Adenosine of the Atrial Muscle
Adenosine on the Atrioventricular NodeAdenosine on the Atrioventricular Node
Control• After • Adenosine• Na+• Ca++• K+• Na+• Ca++• K+• Delayed Rectifier Channel opens during • repolarization resulting in potassium ion • efflux• ATP Dependent Potassium Channel opens • during repolarization resulting in an enhanced • potassium ion efflux that: • • terminates inward calcium ion movement
via the slow inward channel • increases the AV node refractory period • decreases AV node conduction velocity
• Actions of Adenosine of the AV Node
Digitalis Glycosides (Digoxin; Lanoxin™)Digitalis Glycosides (Digoxin; Lanoxin™)
• Actions and Uses: – Complex direct and indirect cardiac actions – Indirect action due to enhanced vagal tone:
• lengthening of AV nodal refractory period • slowing of AV nodal conduction • decrease atrial muscle refractory period • increase atrial muscle conduction velocity
– Antiadrenergic action – Positive inotropic effect
• Uses and Actions (continued) • Atrial flutter and atrial fibrillation - to control
the ventricular response – atrial flutter may convert to atrial fibrillation du
e to effects of increased vagal tone upon atrial refractory period and conduction velocity
• Terminates AV nodal reentrant tachycardia (PAT) after vagal maneuvers and other antiarrhythmic drugs have failed