Arrhythmias. Edward JN Ishac, Ph.D. Heart Physiology. Heart Physiology. Heart Physiology. Ion Permeability. Cardiac Action Potentials Ion Flow

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1 Arrhythmis Edwrd JN Ishc, Ph.D. Closed system Supply nutrients/ Hert Physiology Pressure driven Remove metbolites Smith Building, Room 7 eishc@hsvcu.edu 8-7 or 8-6 Deprtment of Phrmcology nd Toxicology Medicl College of Virgini Cmpus of Virgini Commonwelth University Richmond, Virgini, USA Hert Physiology Hert Physiology P QRS PR T QT - tri depolriztion - ventricle depolriztion - conduction A-V - ventricle repolriztion - durtion ventricle of repolriztion Closed system Pressure driven Supply nutrients/ Remove metbolites P - tri depol. QRS - ventricle depol. PR - conduction A -V T - ventricle repol. QT - durtion ventricle repolriztion Ion Permebility N + C ++.. Crdic Action Potentils Ion Flow N + C ++.. N + i - open N + - close o - open/close C ++ i - open o - lek C ++ - close o - open - close N + i - open N + - close o - open/close C ++ i - open o - lek C ++ - close o - open - close N + /C ++ - exchnge (:) N + / - ATPse (:) N + /C ++ - exchnge (:) N + / - ATPse (:)

2 Chrcteristics of Arrhythmis Definitions: - norml sinus rhythm (6-9bpm), SA node pcemker - rrhythmi; ny bnormlity of firing rte, regulrity or site of origin of crdic impulse or disturbnce of conduction tht lters the norml sequence of ctivity of tri nd ventricles. ccurrence: - 8% of ptients with cute myocrdil infrctions - % of nesthetized ptients - less thn % of ptients on digitlis Clssifiction of rrhythmi. Chrcteristics:. utter very rpid but regulr contrctions tchycrdi incresed rte brdycrdi decresed rte fibrilltion disorgnized contrctile ctivity. Sites involved:. ventriculr tril sinus AV node e. Suprventriculr (tril myocrdium or AV node) Exmples of Arrhythmis Mechnisms of rrhythmis. Abnorml impulse genertion (bnorml utomticity). utomticityof normlly utomtic cells (SA, AV, His) genertion of impulses in normlly non-utomtic cells - development of phse depolriztion in normlly non-utomtic cells - triggered ctivity due to fterdepolriztions - erly fterdepolriztion - delyed fterdepolriztion. Abnorml impulse conduction (more common mechnism). AV block ventricle free to strt own pcemker rhythm Re-entry: re-excittion round conducting loop, which produces tchycrdi - unidirectionl conduction block - estblishment of new loop of excittion - conduction time tht outlsts refrctory period Hert Physiology Unidirectionl Block Closed system Pressure driven Supply nutrients/ Remove metbolites Dmged tissue is usully depolrized fi conduction velocity P - tri depol. QRS - ventricle depol. PR - conduction A -V T - ventricle repol. QT - durtion ventricle repolriztion

3 Strtegy of Antidysrhythmic Agents Suppression of dysrhythmis Clssifiction of Antidysrhythmic Drugs A. Alter utomticity i. decrese slope of Phse depolriztion ii. iii. increse the threshold potentil decrese resting (mximum distolic) potentil B. Alter conduction velocity i. minly the rte of rise of Phse depolriztion i. decrese resting (mximum distolic) potentil ii. decrese membrne responsiveness C. Alter the refrctory period i. increse Phse plteu ii. increse ction potentil durtion Vughn-Willims clssifiction (97), subsequently modified by Hrrison. Helpful, But?. bsed on electrophysiologicl ctions in norml tissue. presumes mechnism of ction of ntidysrhythmic drugs. consists of four min clsses nd three subclsses. does not include ctions of other gents (ie. denosine) Subclss... Clss Clss I Clss IV thers Vughn-Willims Clssifiction Mechnism Moblock Ph.; slow conduction; APD Min.block Ph.; slow conduction; shorten Ph. repolriztion Mrked block Ph.; slow conduction; no chnge APD or repolriztion. cresed suppression of N chnnels Bet blockers; decrese drenergic input. No effect APD, suppress Ph. depolriztion Prolong repolriztion/refrctory period other mens thn exclusively IN block (minly chnnel blockde). C chnnel blockers. Slow conduction nd effective refrctory period in norml tissue (A -V node) nd C-dependent slow responses of depolrized tissue (tri, ventricle, Purkinje) Adenosine, Digoxin, Anticogulnts Prototype Quinidine Procinmide Lidocine Phenytoin Flecinide Encinide Proprnolol others Bretylium Amiodrone Verpmil Diltizem Action Potentil Ion Flow N + N + i - open - close C ++ i - open o - lek C ++ - close o - open N + - close o - open/close C ++.. N + /C ++ - exchnge (:) N + / - ATPse (:) Electrophysiologicl Properties f Specilized Crdic Fibers Quinidine (Clss prototype) Sinus node Automticity AV node Effective refrctory period (ERP) Purkinje fibers,,, CLASS F ANTRRHYTHM DRUG I,,,, IV ther exmples: Procinmide, Disopyrimide. Generl properties:. D-isomer of quinine Among the most common locl nesthetics As with most of the Clss I gents - moderte block of sodium chnnels - decreses utomticity of pcemker cells - increses effective refrctory period/ap durtion Action potentil mplitude,, Phse- Vmx,,,, Action potentil durtion (APD),,,, Effective refrctory period (ERP),,,, ERP/APD Membrne responsiveness, Automticity,,,

4 Crdic effects Actions of Quinidine. utomticity, conduction velocity nd excitbility of crdic cells. Preferentilly blocks open N chnnels Recovery from block slow in depolrized tissue; lengthens refrctory period (RP) All effects re potentitedin depolrized tissues e. creses ction potentil durtion (APD) nd prolongs AP repolriztion vi block of K chnnels; decreses reentry f. direct ction: nticholinergic effect (ccelertes hert), which cn speed A-V conduction. Limited use in treting tril tchycrdi becuse of enhncement of A-V trnsmission to ventricle.. Actions & Toxicity of Quinidine Extrcrdic. Blocks lph-drenoreceptors to yield vsodilttion. ther strong ntimuscrinic ctions Toxicity - "Quinidine syncope"(finting)- due to disorgnized ventriculr tchycrdi - ssocited with gretly lengthened Q-T intervl; cn led to Toursdes de Pointes (precursor to ventriculr fibrilltion) - negtive inotropic ction (decreses contrctility) - GI - dirrhe, nuse, vomiting - CNS effects - hedches, dizziness, tinnitus (quinidine Cinchonism ) Quinidine: Phrmcokinetics/therpeutics. rl, rpidly bsorbed, 8% bound to membrne proteins Hydroxylted in liver; T / = 6-8 h Drug interction: displces digoxinfrom binding sites; so void giving drugs together Probbly re ctive metbolites of quinidine e. Effective in tretment of nerly ll dysrhythmis, including: ) Premture tril contrctions ) Proxysml tril fibrilltion nd utter ) tr-tril nd A-V nodl reentrnt dysrhythmis ) Wolff-Prkinson-White tchycrdis (A-V bypss) f. Especilly useful in treting chronic dysrhythmis requiring outptient tretment Procinmide (Clss A) Crdic effects Similr to quinidine, less muscrinic & lph-drenergic blockde Hs negtive inotropic ction Extrcrdic effects. Gnglionic blocking reduces peripherl vsculr resistnce Toxicity. Crdic: Similr to quinidine; crdic depression Noncrdic : Syndrome resembling lupus erythemtosus Phrmcokinetics/therpeutics. Administered orlly, i-v nd intrmusculrly Mjor metbolite in liver is N-cetylprocinmide (NAPA), wek N chnnel blocker with clss I ctivity. Bimodl distribution in popultion of rpid cetyltors, who cn ccumulte high levels of NAPA. T / = - hours; necessittes frequent dosing; kidney chief elimintion pth. NAPA hs longer T / nd cn ccumulte Usully used short-term. Second choice in CCUs fter lidocine for ventriculr dysrhythmis ssocited with cute MIs Lidocine (Clss prototype) ther exmples: Mexiletine, Phenytoin, Tocinide Generl. Most commonly used ntidysrhythmic gent in emergency cre Given i-v nd i-m; widely used in U-criticl cre units (DC) Very low toxicity A locl nesthetic, works on nerve t higher doses Lidocine Actions Crdic effects. Generlly decreses APD, hstens AP repolriztion, decreses utomticity nd increses refrctory period in depolrized cells. Exclusively cts on N chnnels in depolrized tissue by blocking open nd inctivted N chnnels Potent suppresser of bnorml ctivity Most N chnnels of norml cells rpidly unblock from lidocine during distole; few electrophysiologicl effects in norml tiss ue Toxicity: - lest crdiotoxic, high dose cn led to hypotension - tremors, nuse, slurred speech, convulsions Phrmcokinetics/therpy. i-v, i-m since extensive first pss heptic metbolism T / =.- hours Very effective in supressing dysrhythmi ssocited with depol. tissue (ischemi; digitlis toxicity); ineffective ginst dysrhythmis in norml tissue (tril utter). Suppresses ventriculr tchycrdi; prevents fibrilltion fter cute MI first choice for this ppliction; rrely used in suprventriculr rrythmis

5 Phenytoin (Clss ). Non-sedtive nticonvulsnt used in treting epilepsy ('Dilntin'). Limited efficcy s ntidysrhythmic (second line ntirrythmic). Suppresses ectopic ctivtion by blocking N nd C chnnels. Especilly effective ginst digitlis-induced dysrhythmis. T / = hr - metbolized in liver 6. Gingivl hyperplsi Flecinide (Clss prototype) ther exmples: Lorcinide, Propfenone, decinide, Moricizine Depress rte of rise of AP without chnge in refrctoriness or APD in normlly polrized cells. Decreses APD, decreses utomticity, conduction in depolrized cells.. Mrked block of open N chnnels (decreses Ph. ); no chnge repolriztion.. Used primrily for ventriculr dysrhythmis but effective for tril too. No ntimuscrinic ction. Suppresses premture ventriculr contrctions 6. Associted with significnt mortlity; thus, use limited to lst resort pplictions like treting ventriculr tchycrdis Proprnolol (Clss, bet drenoreceptor blockers) ther gents: Metoprolol, Esmolol, Sotlol(lso Clss I), Acebutolol. Slow A - V conduction Prolong A -V refrctory period Suppress utomticity Crdic Action Potentils Ion Flow N + C ++.. Crdic effects (of proprnolol), non-selective bet blocker. Min mechnism of ction is block of bet receptors; Ph slope. which decreses utomticity under certin conditions Some direct locl nesthetic effect by block of N chnnels (membrne stbiliztion)-t higher doses creses refrctory period in depolrized tissues creses K chnnel current e. creses A -V nodl refrctory period Non-crdic: Hypotension Therpeutics. Blocks bnorml pcemkers in cells receiving excess ctecholmines (e.g. pheochromocytom ) or up-regulted bet-receptors ( ie. Hyperthyroidism) Blocks A - V nodl reentrnt tchycrdis; inhibits ectopic foci Proprnolol used to tret suprventriculrtchydysrhythmis Contrindicted in ventriculr filure; lso cn led to A -V block. N + i - open N + - close o - open/close C ++ i - open o - lek C ++ - close o - open - close rl( proprnolol) or IV. Extensive metbolism in liver. N + /C ++ - exchnge (:) N + / - ATPse (:) Clinicl uses: Bet-Blockers Angin (non-selective or b -selective) - Crdic: demnd more thn supply - Exercise tolernce in ngin ptients Arrhythmi (b -selective, LA-ction) - ctecholmine-induced increses in conductivity nd utomticity Congestive Hert Filure - cution with use Glucom (non-selective) - queous humor formtion (Timolol) ther - block of tremor of peripherl origin (β-ar in skeletl muscle) - migrine prophylxis (mechnism unknown) - hyperthyroidism: crdic mnifesttion (only proprnolol) - pnic ttcks, stge fright b-blockers: Untowrd Effects, Contrindictions Supersensitivity: Rebound effect with β-blockers, less with β- blockers with prtil gonist ctivity (ie. pindolol). Grdul withdrwl Asthm: Blockde of pulmonry β-receptors increse in irwy resistnce (bronchospsm) Dibetes: Compenstory hyperglycemic effect of EPI in insulin-induced hypoglycemi is removed by block of β-ars in liver. β-selective gents preferred

6 Bretylium (Clss I, K+ chnnel blockers) thers Amiodrone, Ibutilide, (Sottol, lso bet-blocker) Generl: originlly used s n ntihypertensive gent Crdic effects. Direct ntidysrhythmic ction creses ventriculr APD nd increses refrctory period; decre ses utomticity Most pronounced ction in ischemic cells hving short APD itilly stimultes nd then blocks neuronl ctecholmine relese from drenergic nerve terminls e. Blocks crdic K chnnels to increse APD Extrcrdic effects: Amiodrone (Clss I) Generl. not frontline, prolongs refrctory period by blocking potssium chnnels lso member of Clsses,,I,IV since blocks N, K, C chnnels nd lph nd bet drenergic receptors second-line gent becuse of its serious side effects effective ginst tril, A-V nd ventriculr dysrhythmis e. very long cting ( d) Hypotension (from block of NE relese) Phrmcokinetics/therpeutics. IV or intrmusculr Excreted minly by the kidney Usully for emergency use only: ventriculr fibrilltion when lidocine nd crdioversion therpy fil. creses threshold for fibrilltion. Decreses tchycrdis nd erly extrsystoles by incresing effective refrctory period Verpmil (Clss IV, C++ chnnel blockers) ther exmple: Diltizem. cresing use nd importnce Blocks ctive nd inctivted C chnnels, prevents C entry More effective on depolrized tissue, tissue firing frequently or res where ctivity dependent on C chnnels (SA node; A-V node) creses A-V conduction time nd refrctory period; directly slows SA nd A-V node utomticity suppresses oscilltory depolrizing fter depolriztions due to digitlis C++ Chnnel Blockers - Actions Extrcrdic. Peripherl vsodilttion vi effect on smooth muscle Used s ntinginl / ntihypertensive Hypotension my increse HR reexively Toxicity. Crdic - Too negtive inotropic for dmged hert, depresses contrctility - Cn produce full A-V block Extrcrdic - Hypotension - Constiption, Nervousness - Gingivl hyperplsi Phrmcokinetics/Therpeutics. T/ = 7h, metbolized by liver rl dministrtion; lso vilble prenterlly Gret cution for ptients with liver disese Blocks reentrnt suprventriculr tchycrdi ( A -V nodl reentrnt tchycrdi ), decreses tril utter nd fibrilltion e. nly modertely effective ginst ventriculr rrhythmis Crdic Effects of Antirrhythmic Drugs Dysrhythmics - thers. Adenosine: i.v. (secs), ctivtes P purinergic receptors (A) coupled to K chnnels, CV, refrctory peroid. Potssium ions (K+): Depress ectopic pcemkers. Digoxin: used to tret tril utter nd fibrilltion - AV node conduction - myocrdium refrctory period - Purkinje fibers refrctory period, conduction.. Autonomic gents: used to tret A-V block - β-gonists, nticholinergics Anticogulnt therpy: - prevent formtion of systemic emboli & stroke Drug Clss Auto CV RP APD ANS effects Quinidine vgl, αα -block Procinmide vgl, αα -block Disopyrmide Lidocine Tocinide Mexiletine Flecinide Propfenone Proprnolol ββ -block Acebutolol ββ -block Esmolol ββ -block Amiodrone I Bretylium I Verpmil IV Digitlis vgl, αα -block other Symptholytic vglstimultion More importnt gents 6

7 Phrmcokinetic Properties of Antirrhythmic Drugs Drug Clss Plsm Binding % T/ (hrs) Drug Excretion Unchnged Quinidine 6 6 -% Procinmide 6% Disopyrmide % Lidocine <% Tocinide % Mexiletine 6 % Flecinide % Propfenone 8 <% Proprnolol 9 <% Acebutolol % Esmolol 9 min <% Amiodrone I 9 dys <% Bretylium I 9 8% Verpmil IV 9 % Dysrhythmi Tretment Agents used in the tretment of HT, CHF, Arrhythmi nd Angin Drug Clss Hypertension CHF Bet-Blockers C++-Blockers ACEI Diuretics Crdic glycosides Vsodiltors Angin Contrindictions/Cutions/Notes Cution: CHF (unstble CHF, bronchospsm, significnt brdycrdi ); or in dibetes, sthm (use ββ -selective) CHF, Gingivl hyperplsi Low GFR, renl stenosis, glossitis, tetrogenic Low GFR, hypoklemi CG; glucose intolernce dibetes Mny Rx interctions, [K+] importnt, low K+ toxicity Flushing, dizziness, hedche, reex tchycrdi N+-Chnnel blockers Nitrtes Arrhyth mi Tolernce, ushing, dizzness, hedche 7