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Agents used in cardiac arrhythmias

Agents used in cardiac arrhythmias. Martin Štěrba, PharmD., PhD. Department of Pharmacology Faculty of Medicine HK, Charles University. Normal conduction within the heart. According to Katzung's Basic & Clinical Pharmacology . McGraw-Hill Medical; 9 edition (December 15, 2003). Aorta.

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Agents used in cardiac arrhythmias

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  1. Agents used in cardiac arrhythmias Martin Štěrba, PharmD., PhD. Department of Pharmacology Faculty of Medicine HK, Charles University

  2. Normal conduction within the heart According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003) Aorta M /1 SA node VC Atrial myocardium 1 AV node SA node Bundle of His Purk. fibre AV node ventricle Bundle of His T ECG P U QRS Time (s) Purkinje fibre 0.2 0.4 0.6

  3. NORMAL ELECTROPHYSIOLOGY OF THE HEART CELLS • Transmembrane potential of cardiac cells is determined by the distribution (concentration) of Na+, K+, Ca2+, Cl- inside/out the cardiac cells • Under resting conditions the inside/out distribution of these ions (namely Na and K) is far from being balanced (homogenous) • Resting membrane potential is -85 mV (+ outside, - inside) • Na+: out 140 mM, inside 10-15 mM • K+: out 4 mM, inside 140 mM (concentration and electrostatic gradients are balanced) • The base for the this inhomogeneous distribution of the ions (charge) is given by impermeability of the sarcoplasmic membrane for ions and the presence of pumps restoring the resting state • Excitation of the myocardium is based on the selective and temporally harmonized changes in permeability sarcoplasmic membrane for given ions (the role of ion channels is crucial)

  4. T-Ca2+ kanál

  5. ARRHYTHMIAS • Electrophysiological abnormalities arising from the impairment of the impulse 1. genesis (origin), 2. conduction, 3. both previous • Arrhythmias are defined by exclusion - i.e., any rhythm that is not a normal sinus rhythm (NSR, 60-100 bpm) is an arrhythmia • With respect to the • Frequency– bradyarrythmias vs. tachyarrhythmias • Localization– supraventricular (SV), ventricular (V) • Mechanism– early afterdepolarisation (EAD), delayed afterdepolarisation (DAD), re-entry CLASSIFICATION 1. Bradyarrhytmias – sinus b., sick-sinus syndrome, AV block 2. Tachyarrhytmias a) Supraventricular (SV) - SV extrasystoles – atrial, junction - atrial tachycardia, flutter, fibrillation - AV node re-entry tachycardia (AVNRT) - AV re-entry tachycardia (Wolf-Parkinson-White syndrome) • b) Ventricular • - ventricular extrasystoles • - ventricular tachycardia • - flutter/fibrillation…

  6. Normal Re-entry According to Katzung's Basic & Clinical Pharmacology. McGraw-Hill Medical; 9 edition (December 15, 2003)

  7. CAUSES OF ARRHYTHMIAS • Myocardial damage • Hypoxia • Ischemia-reperfusion injury • Myocarditis • Cardiomyopathy • Changes in body homeostasis • Electrolyte imbalance– e.g., hypokalemia • Acidobazic imbalance • Hormonal regulation impairments • Thyreotoxicosis • Feochromocytoma • DRUGS! • Virtually all antiarrhytmics possess a proarytmogennic efect!!!!!! • Drug-induced LONG Q-T syndrome

  8. ANTIARRHYTHMIC DRUGS • Classification • Vaughan Williams - 4 major classes • Sicilian Gambit– more precise, well designed, complete, thoughtful but very complicated • Classification according to V. Williams: • Na channel blockers. • Β-blockers • Action potential (AP) prolonging drugs • Ca channel blockers • Other drugs

  9. ANTIARHYTMIC AGENTS Overview of antiarrthythmics CLASS I (Na channels blocker) A)Disopyramide, procainamide, quinidine B)Lidocaine, trimecaine, mexiletine C) Propafenone, flecainide CLASSII (b-blockers) Esmolol Metoprolol Propranolol CLASSIII (K channels blocker) Amiodarone Sotalol Dofetilide Ibutilide CLASS IV (Ca channel blocker) Diltiazem Verapamil Other drug (podle Lippincott´s Pharmacology, 2006) Adenosine Digoxin

  10. I. Class: Na CHANNELS BLOCKER • Primarily they  depolarization velocity (Vmax) in phase 0. • „use dependence“ effect • 3 functional conformations of Na+ channels • resting, activated a inactivated • The effect of these drugs is aimed mainly on activated and inactivated Na channels • Different effect on Vmax (relatively) • I.A medium, I.B lowest, I.C highest • Different effect on AP duration • I. A. – prolongation (slower repolarisation) • I. B. - shortening • I. C. – no significant effects • Presence of antimuscarinic and negative inotropic effects (as e.g. IA)

  11. Class I.a quinidine, procainamide, disopyramide Class I.b mesocaine, lidocaine, mexiletine, phenytoine Class I.c propafenon, flecainide, encainide

  12. I.A Class:QUINIDINE • Relatively broad spectrum of antiarrhythmic effects • Optical isomer of the quinine • Today rather obsolete drug • Cardiac effects: • AP •  QT interval • negative inotropic • parasympatholytic • Vasodilating effect • PK:oral route, liver metabolism, t1/2= 6 hod, CYP450 3A4 • Indications:currently very limited • Rather in past: prophylaxis of the supraventricular (exceptionally ventricular) arrhythmias, pharmacological cardioversion of the AF

  13. I.A Class:QUINIDINE • Adverse effects (common and serious) • GIT– diarrhoea, nausea, vomiting (in up to 30% of treated patients) • CNS – „cinchonisms“ – headache, vertigo, tinnitus, visual disturbances • haematological - thrombocytopenia, haemolytic anaemia) • skin– urticaria (rash), photosensitisation • Myalgia, arthralgia, lupus-like sy., fever, hepatitis • Cardiovascular system • Induction of ventricular tachycardia (Torsades de pointes) • Decreased ventricular contractility, HF precipitation • Bradycardia, heart arrest • Interactions:strong inhibitor of CYP 2D6 (anticoagulantia) • ContraInd.:AV block, symptomatic HF, long QT, thrombocytopenia, gravidity and lactation

  14. Drugs affecting quinidine metabolism Drugs stimulating its metabolism phenytoine rifampicine Barbiturates + Inactive metabolite Quinidine Drugs inhibiting its metabolism Ketoconazole (podle Lippincott´s Pharmacology, 2000)

  15. I.A Class: PROCAINAMIDE • ↓ antimuscarinic action • ↑↑ negative inotropic action • Pharmacokinetics • Metabolised (15-30 %) to N-acetylprocainamide (NAPA) • NAPA active metabolite is excreted by kidney (similarly as parent. c) • Gene polymorphism - slow acetylators: decrease the dose ( lupus risk) • - rapid acetylators: NAPA cumulation – TdP risk • Indications:like quinidine, rarely used, rather short treatment (lupus) • Adverse and toxic effects • Hypotension, esp. after faster i.v. infusion. • Long QT syndrome a TdP • Lupus-like syndrome: after long treatment (> 6 months): • arthralgia, arthritis, rarely also inner organs (pleuritis, pericarditis, pneumonia, interstitial nephritis). • Syndrome disappear spontaneously after drug withdrawal • Other: GIT (vomiting, diarrhoea), allergy, CNS (depressions, hallucinations), haematological disturbances

  16. I.A Class: DISOPYRAMIDE • Similar PD as quinidine • Negative inotropic a antimuscarinic effects are even more pronounced • Metabolised in the liver • Metabolites are responsible for antimuscarinic effects • Excreted by kidney (50% as metabolites) • Indication: as in quinine • Adverse reactions: • antimuscarinic (dry mouth, visual disturbances, urinary retention, glaucoma worsening) • neg. inotropic – can precipitate HF

  17. I.B Class: MESOCAINE, LIDOCAINE, MEXILETINE • Synthetic local anaesthetics + related compound (mexiletine) • PK • ONLY i.v. administration • After p.o.  first pass effect (80-97 %) • Liver metabolism • t1/2 = 90 min • Indications • Acute ventricular tachyarrhythmias after M.I. and in cardiac surgery • However, should not be given routinely as a general prophylaxis during acute M.I. treatment. Risk vs. benefit! • Ventricular arrhythmias associated with digoxin overdose • Adverse reactions:quite acceptable and often predictable with appropriate dosing • CNS – paresthesia, tremor, nausea, hearing and speaking disturbances • In high doses - agitation and convulsions may appear(treatment - diazepam), apnoea, negative inotropic action andhypotension

  18. I.B Class:PHENYTOINE • Antiepileptic drug with cardiac effects similar to mesocaine • IND:supraventricular and ventricular tachyarrhythmias,esp. those associated with digoxin intoxication • PK • p.o. a i.v. route, saturable metabolism in the liver (0. order PK), potent inductor of the liver enzymes • Adverse reactions • neurological disturbations (ataxia, vertigo, nystagm) • megaloblastic anaemia • Hirsutism and gum hypertrophy,

  19. I.C Class:PROPAFENONE • PD: besides Na blocking effects • Weak Ca channel blocker • weak β-blocker • PK: metabolized to active metabolites • Genet. polymorphism – slow metabolizers may have even 2x higher Cmax and 3x longer T1/2 • Ind: SV tachyarrhythmias (WPW, AV node re-entry tachycardia,paroxysmal atrial fibrillation) and some ventricular arrhythmias • Adverse effects • Cardiac – AV or bundle branch blockades, ventricular tachyarrhythmias • GIT – Nauzea, vomiting, constipation and metallic taste • CNS – tremor, restlessness, headache, sleeping disturbances • Flecainide, encainide

  20. II. Class: BETA-BLOCKERS • Pacemakers: decrease the rate of the spontaneous firing • prolong AV conduction • Decrease resting membrane potential (it is more negative) – negative bathmotropic effects • Clinical correlates •  TF •  impulse conduction to ventricles •  threshold for ventricular fibrillation • Improved prognosis of patient after M.I. (sudden death prevention – antiarrhythmic effects) • PK differences – t1/2! • esmolol, metoprolol, propranolol…

  21. TŘÍDA III. (podle Lippincott´s Pharmacology, 2006)

  22. III. Class: DRUGS PROLONGING AP (K channel blockers) • Amiodarone • Significantly prolongs the AP and ERP of Purkinje fibers and ventricular myocardium • Complex PD: • Inhibition of K+, Na+ and Ca2+ channels, b1-blockade • Indication: relatively broad spectrum • Serious ventricular tachyarrhythmias • Hemodynamically significant atrial flutter and fibrillation, WPW… • PK (very specific) • i.v. (acute), can also be given p.o. but BAV is quite low and can be variable (20-60%) • Liver metabolism to active metabolite • Elimination – „early“ (3-10 days, 50 % of the drug), second phase several weeks (acute admin. 40 days, in Css up to 100 days) • Interaction – CYP 3A4 inhibitors/inductors (e.g. cimetidin a rifampicin)

  23. III. Class:AMIODARONE • Adverse and toxic effects • Cardiac • bradycardia, AV blockade • long QT syndrome and TdP risk • Extracardiac • Lungh fibrosis (in a serious form in up to 1% of patients) • Hepatotoxicity • Skin deposits – fotodermatitis and coloured sun-exposed skin (blue-grey) • Corneal microdeposits – detectable already after few weeks of treatment, it's mostly asymptomatic, but may cause blurred vision in some patients • Optic neuropathy/neuritis (rare) may result in blindness • Thyreoidal dysfunction: mostly hypofuction but hyperfunction can also occur (mechanism?... block T3 to T4 conversion, large doses of I in the drug molecule

  24. III. Class: SOTALOL • III. class antiarrhythmic drug with b-blocking effects • L-isomer (non selective b-blocker without ISA), • Both D and L isomers - III. class antiarrhythmic drug • Isolated D-isomer was not as efficient as racemate • PROLONG AP:block rapid outward K current repolarization phase is slowed – i.e., prolonged,  longer is also effective refractory period (EPR) • IND:i.v. - serious ventricular and SV arrhythmias • P.o. - effective in prophylaxis of recurrent SV arrhythmias • To keep the sinus rhythm after cardioversion of AF •  threshold for ventricular fibrillation, •  occurrence of ectopic beats • PK: relatively simple and predictable (p.o. i i.v.) –limited risk of drug interactions • Adverse reaction: generally relatively tolerable drug (mostly transient) • Riskfull is the induction of the long QT due to the possibility of TdP occurrence (the risk in approx. in 3-4 % patients) • Bradycardia, HF precipitation, hypotension, bronchoconstriction, sleep disturbances (KI: severe HF, asthma..)

  25. III. Class • Dofetilide • Used in patients with persisting AF to maintain sinus rhythm • Proarrhythmogenic – TdP, the QT monitoring is essential • Ibutilide • Similar as dofetilide • but indicated mainly for rapid pharmacological cardioversion of AF and Flutter to sinus rhythm

  26. IV. Class: Ca CHANNEL BLOCKERS • The effects on slow response structures (SA and AV nodes) • - conduction is based on Ca •  depressed spontaneous depolarization of SA node • decreased AV node conduction • decreased ventricular response in AF and flutter • suppress AV nodal re-entry tachyarrhythmia • x no major impact on ventricular tachyarrhythmias • Rapid response structures (the rest of the myocardium) •  Ca2+ channel block (L- type) in 2nd AP phase less Ca for contraction -negative inotropic response

  27. IV. Class:VERAPAMIL, DILTIAZEM • Indication: SV tachyarrhythmias (for AF termination or to decrease the ventricular response) • Adverse reactions: mostly well predictable • AV block, negative inotropic effect can cause precipitate HF, BP decrease • In patients with AF coupled with sustained ventricular tachycardia – verapamil i.v. can cause hemodynamic collapse • extracardiac: constipation, headache, vertigo • Contraind:hypotension, AV block of higher degree, WPW syndrome, HF • Interaction:do not combine with beta-blockers (i.v.) – risk of AV blocks and cardiac arrest or acute HF

  28. Some adverse effects of Ca channels blockers (podle Lippincott´s Pharmacology, 2006)

  29. OTHERS • Cardioglycosides (digoxin) • negative dromotropic and chronotropic effect– due to the central stimulation of the n. vagus → markedly slowed AV conduction important for control of the ventricular response in AF and flutter • Indication: atrial fibrillation and flutter – esp. When rapid ventricular response is associated with HF symptoms • Mg, K • Indication:digoxin-induced tachyarrhythmias and Torsades de pointes (TdP)

  30. OTHERS • Adenosine (endogenous purin nucleotide) • blocks A1 receptors • the most significant effect is on slow response structures: • SA and AV node – inhibition of the Ca current •  decreased SA node firing and mainly AV conductivity • i.v. only • PK:extremely short t1/2 < 10 s • Indication: rapid and effective management of AV nodal re-entry tachycardia (successful in 90-95%) • Adverse reactions: flush, headache, dyspnoea (bronchoconstriction), chest pain, palpitations, very rare is induction of ventricular fibrillation • Drugs in bradyarrthytmias • antimuscarinic • beta-sympathomimetics

  31. NOTES TO PHARMACOTHERAPY OF ARRYTHMIAS • Generally limited options in bradyarrhythmias (acute: atropine, ipratropium), esp. in chronic forms • The approach to antiarrhythmic treatment has changed a LOT in recent years – evidence based medicine ! • Aggressive treatment aimed on complete correction of ECG abnormalities back to normal is not accepted any more as a reasonable treatment end-point • The elder drugs with known risks and without clear proof of efficacy are being abandoned • The enormous development in the field of non-pharmacological treatment changes the point of view • Direct current cardioversion, Implantable cardioverter-defibrilator, catheterisational radiofrequency ablation, modern approaches of cardiac surgery

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