Agents used to treat Arrhythmias

1. Agents used to treat Arrhythmias Dr. Thomas Abraham PHAR417: Fall 2005

2. Review of Cardiac Electrophysiology • Route of electrical conduction through the heart. • -electrical impulses conducted through specialized conduction cells and electrically coupled myocytes. • - SA node --- atrial body --- AV node --- bundle of His --- bundle branches --- purkinje fibers --- ventricular myocardium. Sympathetic nerves supply the SA node, the atrial body, AV node, His-Purkinje fibers and the myocardial cells to enhanced electrical conduction throughout the heart. Parasympathetic nerves supply the SA node, some atrial body and AV node to decreased electrical conductivity through the heart.

3. Review of Cardiac Electrophysiology • Generation of spontaneous depolarization at the sinoatrial (SA) node: • The resting membrane potential of cardiac cells is predominantly determined by the distribution of K+ ions on either side of the membrane. • Cardiac rhythm is initiated at specialized excitable cells within the Sinoatrial node. • The membranes of the SA nodal cells are leaky to calcium (and sodium) ion and this causes a slow increase in the membrane potential from about –60 to –45 mV (phase 4). Once the threshold voltage is achieved the membrane depolarizes and the voltage-dependent calcium channels are opened.

4. Review of Cardiac Electrophysiology • Influx of calcium causes the membrane to depolarize toward 0 mV potential (phase 0) and as the calcium channels slowly inactivate (phase 2) the potassium channels are opened and K+ ion efflux results in membrane repolarization (phase 3) and hyperpolarization. • Since the membranes in these cells are leaky to calcium they continually allow calcium in and the membrane potential rises toward threshold (phase 4 again) and the action potential cycle is repeated again. • Heart rate is increased by adrenergic (NE) stimulation of b1-receptors on SA nodal cells that leads to increased rate of phase 4 depolarization, lowering of threshold potential and increased rate of phase 3 repolarization.

5. Review of Cardiac Electrophysiology Electrical activity of cells of the conduction system and myocardial cells • Sympathetic nerve activity at the AV node and conduction system increases the rate of transmission of electrical impulses from the SA node to the ventricles. • Depolarization and action potential overshoot of Purkinje and ventricular muscle cells requires initial sodium channel opening and sodium ion influx (phase 0) followed by rapid Na+ channel inactivation and K+ channel opening (phase 1) and opening of calcium channels (phase 2).

6. Review of Cardiac Electrophysiology Electrical activity of cells of the conduction system and myocardial cells • Calcium ion influx helps maintain membrane voltage in depolarized state (phase 2) until delayed rectifier potassium channels are activated and K+ ion efflux (phase 3) repolarizes the membranes. • In nodal cells and conduction fibers increased rate of electrical impulse transmission (due to sympathetic nerve activity) involves enhanced depolarization and repolarization rates: i.e. decreased duration of the resultant action potential.

7. Review of Cardiac Electrophysiology Electrical activity of cells of the conduction system and myocardial cells Activation of specific K+ channels by acetylcholine through M2-muscarinic receptors results in decreased resting membrane potential (hyperpolarization); results in decreased spontaneous depolarization of autoarrhythmic cells and decreased conduction rate through atria and AV node.

8. Review of Cardiac Electrophysiology Characteristic of the action potential from various regions of the heart and the resultant composite electrocardiogram (ECG): PR interval: QRS interval: QT interval:

9. Review of Cardiac Electrophysiology • Na+ channel activity affects threshold potential; blockade results in decreased conduction velocity, increased QRS duration, decreased phase 4 depolarization rate. • K+ channel activity determines resting potential and action potential duration; blockade results in increased APD. • Ca2+ channel activity in slow response tissues (nodal cells) allows spontaneous depolarization; blockade decreases heart rate, AV conduction rate, increases PR interval.

10. Anti-arrhythmic Agents General classification and mechanism of action of Antiarrhythmic drugs ·Drugs classified according to their general eletrophysiological effects on cardiac action potential: -developed by Vaughan Williams (1989) -Class I agents: inhibit Na+ channels; membrane stabilizing. -Class II agents: b-adrenergic receptor antagonists. -Class III agents: prolong action potential duration, K+ channel blockers. -Class IV agents: Ca2+ channel blockers.

11. Anti-arrhythmic Agents • All arrhythmias are thought to be due to defects in action potential initiation or conduction. • Spontaneous depolarization reduced by: • (1)decreased rate of phase 4 depolarization • (2)increased threshold • (3)increased maximum diastolic potential • (4)increased action potential duration • refractoriness can be increased by increasing ERP • (1)blockade of Na+ channels • (2)blockade of K+ channels

12. Anti-arrhythmic Agents Spontaneous depolarizations can be decreased by: • decreasing the slope of phase 4 depolarization by interfering with the leakyness of membranes. • increasing the threshold potential by altering membrane leakyness to Na+ or Ca2+ ions (depending on tissue). • hyperpolarizing the membrane by activating K+ currents. • increasing the action potential duration by inhibiting K+ efflux.

13. Anti-arrhythmic Agents Na+ channels cycle through three distinct states during the course of the action potential of the conducting or myocardial cell: OPEN During phase 0 CLOSED During phase 4 INACTIVE During phases 1-3

14. Anti-arrhythmic Agents Increased refractoriness of cardiac cells may be achieved by: • Na+ channel blockade increases the effective refractory period by decreasing the number of channels that are in the closed state (ready for depolarization). • K+ channel blockade increases the time taken for cell membranes to return to more negative potentials and thus Na+ channels will remain in the inactive state longer.

15. Class IA Antiarrhythmic Agents (quinidine, procainamide, disopyramide) Quinidine (Quinaglute®, Quinidex®) • From the cinchona bark; (+) isomer of quinine: quinoline ring and bicyclic quinuclidine ring both basic and can form salt conjugates (sulfate, gluconate, polygalaturonate). • : • Well absorbed from GI tract after oral administration; ~80% bound to plasma proteins • Extensive hepatic metabolism to 3-hydroxyquinidine (only slightly less potent than quinidine).

16. Class IA Antiarrhythmic Agents (quinidine, procainamide, disopyramide) Quinidine (Quinaglute®, Quinidex®) • Major therapeutic effect achieved (at lower doses) by Na+ channel (in the open state) and delayed rectifier K+ channel blockade: increases threshold potential (Na effect) and prolongs APD to prolong refractoriness and decrease automaticity. ECG effects: prolong QRS complex and QT interval. • Has significant effects to antagonize a-adrenergic receptors and decreases vagal tone to the heart.

17. Class IA Antiarrhythmic Agents Quinidine: • Used to maintain normal sinus rhythm in pts. with atrial flutter/fibrillation and ventricular tachycardias. • Noncardiac adverse effects: diarrhea, thrombocytopenia, hepatitis, bone marrow suppression, lupus syndrome, cinchonism (headaches, tinnitus), asthma; • Cardiac adverse effects: QT elongation & torsades de pointe; ventricular tachycardia due to vagolytic effect, syncope, heart failure.

18. Class IA Antiarrhythmic Agents Quinidine: • Drug interactions: • potentiate effect of NM blockers and worsen myasthenia gravis; • potentiate effects of anticholinergic drugs to worsen PSVT • Urine alkalization (carbonic anhydrase inhib., thaizides, antacids, bicarb) decreases excretion; • potentiate effects of antihypertensives; • By a-bloc • increases plasma digoxin due to decreased renal clearance.

19. Class IA Antiarrhythmic Agents Procainamide (Pronestyl®, Procan®) • Amide derivative of procaine, developed to be more resistant to esterase metabolism and have oral activity. • Rapid renal elimination of unchanged drug; hepatic metabolism (conjugation) to N-acetyl procainamide • Blocks Na+ channel (in open state) to decrease automaticity and block K+ channels to prolong APD: decreases conduction velocity and prolongs QRS. No vascular effects.

20. Class IA Antiarrhythmic Agents Procainamide (Pronestyl®, Procan®) • N-acetyl procainamide has no Na+ channel blocking activity but prolongs APD. • Adverse effects: hypotension (I.V. admin.), potentially fatal bone marrow depression, lupus-like syndrome.

21. Class 1B Antiarrhythics (lidocaine, tocainide, mexiletine, phenytoin) Lidocaine (Xylocaine®) •      Metabolized to monoethyl form and cleaved by amidase to glycine xyladine • First-pass metabolism prevents oral therapeutic doses without toxicity; IV admin. onset of action 45-90 sec with 10-20 min duration. Due to biexponential elimination from plasma bolus dose effect can be lost as drug partitions into tissues –loading and maintenance dosing adjusted to avoid this. • Blocks both open and inactive states of Na+ channel but prefers inactive state; rapid blockade recovery allows greater effects in depolarized or rapidly driven tissues. • Controls ventricular arrhythmias by decreasing automaticity of His-Purkinje system and ventricles. Used to control ventricular arrhythmias, PVCs due to MI and digitalis-induced ventricular arrhythmias.

22. Class 1B Antiarrhythics (lidocaine, tocainide, mexiletine, phenytoin) Lidocaine (Xylocaine®) • Blocks both open and inactive states of Na+ channel but prefers inactive state; rapid blockade recovery allows greater effects in depolarized or rapidly driven tissues. • Controls ventricular arrhythmias by decreasing automaticity of His-Purkinje system and ventricles. Used to control ventricular arrhythmias, PVCs due to MI and digitalis-induced ventricular arrhythmias.

23. Class 1B Antiarrhythics • Appears to shorten the APD but increases the ERP of ventricular cells. Has little effect on PR interval or QRS duration; QT interval not altered much and little hemodynamic effects. • Hepatic metabolism to mono-ethylxyladine a less potent Na+ channel blocker which competes with parent for binding sites. • Adverse effects: drowsiness, disorientation, paresthesias, muscle twitching, agitation, anxiety. More severe psychosis, respiratory depression and seizures can occur at higher doses. • Tocainide (Tonocard®) is a structural analog of monoethyl xyladine (lidocaine metabolite) with good oral activity and used in the treatment of ventricular arrhythmias. Similar adverse effects as lidocaine. Mexiletine (Mexitil®) has similar uses and adverse effects as lidocaine and tocainide; unlike lidocaine has good oral bioavailability.

24. Class 1B Antiarrhythics • Tocainide (Tonocard®) is a structural analog of monoethyl xyladine (lidocaine metabolite) with good oral activity and used in the treatment of ventricular arrhythmias. Similar adverse effects as lidocaine. Mexiletine (Mexitil®) has similar uses and adverse effects as lidocaine and tocainide; unlike lidocaine has good oral bioavailability.

25. Class 1B Antiarrhythics (lidocaine, tocainide, mexiletine, phenytoin) • Phenytoin (Dilantin®) • Strong electron-withdrawing carbonyl groups cause proton-donating activity in the N in between. • Solubility is improved by highly alkaline vehicle (pH 12). • Has good oral activity, also administered IV; high first-pass metabolism after oral dose. High plasma-protein binding (~90%) can be altered by competing drugs and renal disease.

26. Class 1B Antiarrhythics (lidocaine, tocainide, mexiletine, phenytoin) Phenytoin (Dilantin®) • Can induce hepatic metabolism of other drugs (e.g. quinidine, digitoxin, estrogens, theophylline) • Blocks inactive Na+ channels of ventricles and conduction system. Used in the therapy of ventricular arrhythmias, including those due to digitalis toxicity. • Adverse effects: ataxia, tremors, nystagmus, blurred vision, sedation, bone marrow suppression.

27. Class 1C Antiarrhythics • Flecainide (Tambocor®) • Fluorinated benzamide derivative. • Blocks Na+ channels and delayed rectifier K+ channels to prolong PR interval, QRS duration and QT interval. Prolongs AP in atria at fast beats. • Adverse effects: (noncardiac) blurred vision; (cardiac) can exacerbate heart failure and heart block, initiate potentially lethal arrhythmias. • Has good oral absorption. Elimination by renal route of unchanged drug and hepatic metabolism.

28. Class 1C Antiarrhythmics Propafenone (Rhythmol®) • Has Na+ channel and maybe some K+ channel • blocking capacity to decrease conduction • in fast response tissue (prolongs PR interval and QRS duration). • Can be administered orally to maintain sinus rhythm in SVTs and VT. • Drug is racemic mixture with both isomers being Na+ channel blockers but S-(+)-isomer also has some b-adrenergic receptor blocking capacity. Primary metabolite (5-hydroxypropafenone) has similar Na+ channel blocking activity as parent. • Adverse effects: dizziness, metallic taste, nausea, vomiting and proarrhythmic actions. Can increase doses of warfarin, digoxin and metoprolol upon coadministration (>95% protein binding).

29. Class II Antiarrhythmic agents (propranolol, esmolol, metoprolol) Propranolol (Inderal®) • Non-selective b-adrenergic receptor antagonist that • decreases adrenergic component of arrhythmias: • decreases rate of phase 4 depolarization to • decreased automaticity and conduction velocity of conduction cells and myocardial tissue; some increase in PR interval, prolong QRS. • The d-isomer may have ‘membrane-stabilizing’ effects apart from b-blockade. May be facilitated by high lipid:water partition coefficient. • Adverse effects: precipitate heart failure, ventricular asystole (decreased AV conduction), hypotension, hypoglycemia, bronchospasms. • Esmolol (Brevibloc®) • rapid metabolism by serum and hepatic esterases requires IV administration. • Has b1-selective effects to produce antiarrhythmic affects.

30. Class III antiarrhythmic agents (sotalol, amiodarone, bretylium) • Sotalol (Betapace®) • Racemic mixture of d and l-forms in preparation. • L-isomer has significant b-receptor blocking ability while both d- and l-forms have equivalent K+ channel blocking activity • Renal excretion of unchanged drug; renal impairment can result in toxicities. • Has effects to prolong the action potential duration throughout the heart and prolong the QT interval (K+ channel blockade). Decreases automaticity, slows AV conduction rate and prolongs AV refractoriness (b-blockade and K+ channel blockade). • Adverse effects: can cause arrhythmias (torsades de point) especially with hypokalemia; similar to other b-blockers.

31. Class III antiarrhythmic agents (sotalol, amiodarone, bretylium) Amiodarone (Cordarone®) • Structural analog of thyroid hormone; has high lipid:water • partition coefficient and tend to concentrate in tissues. • Blocks inactivated Na+ channels, Ca2+ channels and K+ channels. Also a- and b-adrenergic blockade. • Inhibits abnormal automaticity and prolongs APD; decreases conduction velocity by Na channel block and “nonspecific” effects. Prolongs PR, QRS and QT intervals and refractoriness. • Adverse effects: hypotension, pulmonary fibrosis, corneal microdeposits, hypo- and hyperthyroidism, photosensitivity, muscle weakness.

32. Class IV antiarrhythmic agents (verapamil, diltiazem) Verapamil (Calan®) • ·Phenylalkylamine calcium channel blocker with relatively high activity at cardiac calcium channels. • ·Calcium channel block results in decreased rate of phase 4 depolarization, rate of rise of AP and maximum depolarization to have negative chronotropic effects at SA node. • ·Decreases AV conduction velocity by decreasing calcium channel activity to prolong PR interval. • ·Adverse effects: constipation, sinus arrest, hypotension, headache, nervousness.

33. Miscellaneous antiarrhythmic agents • Digoxin (Lanoxin®) • Inhibitor of Na-K-ATPase pump that has positive ionotropic effects on myocardium. • Increases phase 4 depolarization rate (increased automaticity) and decreased AV conduction rate (increased vagus nerve stimulation). • Adenosine (Adenocard®) • Naturally occurring nucleoside that activates K+ channels (similar to acetylcholine) in SA and AV nodes. • Causes hyperpolarization of automatic cell membranes (decreases normal rhythm) and decreased conduction through AV node.