Dr. IshacAntidysrhythmic Agents1

Cardiovascular Pharmacology - Antidysrhythmic Drugs

Edward JN Ishac, Ph.D.

Professor, Pharmacology and Toxicology

Smith 742, 828-2127, e-mail:

OBJECTIVES

  1. Understand how, in general antidysrhythmic drugs suppress electrical disorders that result from problems in cardiac impulse generation or conduction
  2. Recognize how drugs differentially suppress firing in abnormal vs. normal cardiac tisssue
  3. Recognize concept of state dependent drug action and it’s significance for antidysrhythmic action
  4. Recall the Vaughan-Williams classification of antidysrhythmic drugs and its limitations
  5. Be able to cite prototype drugs from each of the four Vaughan-Williams classes.
  6. Understand the mechanism of action/electrophysiological effects, autonomic effects, pharmacokinetic effects, toxicity and non-cardiac actions of the prototype drugs.
  7. Know names of each non-prototype and uniqueness of each one.
  8. Understand representative clinical uses of each class.

I.Brief review of physiological concepts:

a.The heart contains specialized cells that exhibit automaticity, ie. generate rhythmic action potentials in the absence of external stimuli (sino-atrial node, AV node). Optimal mechanical performance requires well-synchronized repetitive electrical activity Fig. 1).

Figure 1.

c.Sino-atrial node (SA) sets the pace (ie. pace maker) for the electrical activity of the heart

d.The response of cells to excitatory electrical stimuli is a function of the number of available sodium (Na) channels. An index of the number of open Na channels is dV/dt (of Phase 0) of the cardiac action potential (AP).

d.Abnormal heart tissue is usually depolarized, which reduces Na current, decreases dV/Dt and decreases conduction velocity.

e.Voltage-dependent Na channel availability results from Voltage (Vm) -dependent Na channel states. Recovery time of Na channels from excitation/depolarization strongly contributes to the refractory period and is increased by many drugs (See Fig 2).

Figure 2: What this means:

1. Conduction in damaged/abnormal heart tissue is decreased

2. Antidysrhythmics work better on Na channels in depolarized cells and decrease recovery.

II.Characteristics of dysrhythmias

1.normal sinus rhythm (60-100bpm), set by SA node pacemaker

2.arrhythmia; any abnormality of firing rate, regularity or site of origin of cardiac impulse or disturbance of conduction that alters normal sequence of activity of atria and ventricles.

Classification of dysrhythmias, characteristic or sites involved:

1.characteristics:

a.flutter – very rapid but regular depolarizations

b.tachycardia – increased rate

c.bradycardia – decreased rate

d.fibrillation – disorganized depolarization activity

2.sites involved:

a.ventricular

b.atrial

  1. sinus
  2. AV node
  1. Supraventricular (atrial myocardium or AV node)

Schematic diagram of ion permeability

III.Mechanisms of arrhythmias

1.Abnormal impulse generation (abnormal automaticity)

a.automaticity of normally automatic cells (SA, AV, His)

b.generation of impulses in normally non-automatic cells

  1. phase 4 depolarization in normally non-automatic cells
  2. ‘triggered activity’ due to afterdepolarizations

-early afterdepolariztion (EADs)

-delayed afterdepolarization (DADs)

2.Abnormal impulse conduction (more common mechanism)

- damaged tissue usually depolarized conduction velocity

a.AV block – ventricle free to start own pacemaker rhythm

b.Re-entry: re-excitation around a conducting loop, which produces tachycardia

  1. unidirectional conduction block
  2. establishment of new loop of excitation
  3. conduction time that outlasts refractory period

IV.General strategy of antidysrhythmic drugs

Suppression of dysrhythmias

A.Alter automaticity (usually want to decrease)
i.decrease slope of Phase 4 depolarization
ii.increase the threshold potential
iii.decrease resting (maximum diastolic) potential

B.Alter conduction velocity (usually want to decrease)
i.mainly via decrease slope of Phase 0 upstroke

ii.decrease rate of rise of Phase 4 depolarization
ii.decrease membrane resting potential and responsiveness

C.Alter the refractory period (usually want to increase)
i.increase Phase 2 plateau

ii.increase Phase 3 repolarization
iii.Increase action potential duration

IV.Classification of Antidysrhythmic Drugs

A.Vaughan-Williams classification (1970), subsequently modified by Harrison.

1.based on the pattern of electrophysiological actions in normal tissue

2.presumes a mechanism of action of antidysrhythmic drugs

3.consists of four main classes and three subclasses

4.does not include agents (ie. Adenosine, digoxin) that act at other sites

Table 1. Class I- directly block Na channels. All behave like local anaesthetics. Subclasses based on differing effects on AP duration (APD) and degree of Na channel block (Phase 0).

Subclass / Mechanism / Examples
IA. / Na channel blockers
Moderate block Ph.0; slow conduction; increase APD / Quinidine
Procainamide
IB. / Na channel blockers
Minimal block Ph0; slow conduction; shorten phase 3 repolarization, decrease APD / Lidocaine
Tocainide
Phenytoin
IC. / Na channel blockers
Marked block Ph.0; slow conduction.; no change APD or repolarization. Increased suppression of Na channels / Flecainide
Encainide
Class II / Beta blockers
decrease adrenergic input . No effect APD, suppress phase 4 depolarization, slow conduction. / Propranolol
Metoprolol
Sotalol
others
Class III / K channel blockade
Prolong repolarization/refractory period other means than exclusively INa block (mainly K channel blockade), ↑QT. / AmiodaroneSotalol
Bretylium
Class IV / Ca channel blockers
Slow conduction and increase effective refractory period in normal tissue (A-V node) and Ca-dependent slow responses of depolarized tissue (atria, ventricle, Purkinje) / Verapamil
Diltiazem
Nifedipine
Others / Adenosine, Digoxin, Mg and K ions / Not part of VW table
  1. Shortcomings of Vaughan-Williams system (V-W):
  1. The classification (excluding Class II) is mainly based on drugs which modify the electrophysiological characteristics of normal cardiac tissue. In diseased tissue, where dysrhythmias are more likely to occur, channels and receptors, and their responses to drugs, are modified.
  2. V-W is incomplete, and does not include adenosine, digitalis, cholinergic agonists, alpha adrenergic blockers or agents that modulate gap junctions, ion pumps or exchangers. It also ignores actions of metabolites of the drugs.
  3. Some drugs have properties of several classes (amiodarone, for example, has properties of classes I-IV).
  1. Key Aspects of Antidysrhythmic Drug Action and Therapy
  1. Antidysrhythmic drug action is state-dependent; drug effects depend on the molecular states of the channel (i.e. open, closed, or inactivated). Two current models:
  2. modulated receptor hypothesis: different states have different affinities
  3. guarded receptor hypothesis: channel gate limits drug access to site
  4. Dysrhythmic drugs selectively affect firing and CV in abnormal/depolarized cells..
  5. Since transitions between different states are dependent on membrane voltage and cell firing frequency, drug action is also dependent on membrane voltage and spike frequency. In addition, by binding to inactivated states and slowing recovery from inactivation, some drugs can increase the time needed for recovery from inactivation.
  6. Can be prodysrhythmic under certain circumstances
  7. May have significant cardiac and extracardiac toxicity; many Class 1A drugs, for example, can seriously depress cardiac contractility directly by acting on heart muscle
  8. often affect the autonomic nervous system, and have hemodynamic effects and effects on cardiovascular reflexes
  1. Antidysrhythmic drugs also selectively affect different parts of the heart
  1. Ca channel blockers (Class IV) are selective for A-V and S-A nodes, where Ca action potentials predominate. This explains why Class IV drugs are so useful for treating A-V re-entrant tachycardias for example.
  2. Lidocaine (Class IB) has been useful for treating PVCs in Purkinje fibers, since longer APDs in Purkinje yield more inactivated Na channels. Lidocaine selectively blocks inactivated state Na channels. Lidocaine has little effect, in constrast, on atrial tissue.
  3. Quinidine affects both atrial and ventricular dysrhythmias (but has been mostly used to treat atrial fibrillation).

DRUGS USED FOR DYSRHYTHMIAS

  1. Specific examples of drugs from each Vaughan-Williams class and their key aspects

A.Quinidine (ClassIA prototype; others: Procainamide, Disopyrimide)

1.General properties:

a.use decreasing, significant side effects

b.an alkaloid, D-isomer active

c.As with most of the Class I agents

- moderate block of sodium channels

- decreases automaticity of pacemaker cells

- increases effective refractory period/AP duration

2.Cardiac effects of quinidine

a.Decreases automaticity, conduction velocity and excitability

b.Preferentially blocks open Na channels

c.Recovery from block slow in depolarized tissue; lengthens refractory period

d.All effects are potentiated in depolarized tissues

e.Increases action potential duration (APD) and prolongs AP repolarization via block of K channels; decreases reentry, ↑QT

f.Indirect action: anticholinergic effect (accelerates heart), which can speed A-V conduction.

3.Extracardiac

a.blocks alpha-adrenoreceptors to yield vasodilatation.

b.blocks muscarinic receptors (ie. blurred vision, dilated pupils)

4.Adverse Effects/Toxicity

a.Cardiac

- "Quinidine syncope"(fainting)- due to disorganized ventricular tachycardia

- associated with greatly lengthened Q-T interval; can lead to Torsades de Pointes (TdP, precursor to ventricular fibrillation)

- negative inotropic action (decreases contractility)

b.Extracardiac

- GI - diarrhea, vomiting

- CNS - headaches, nausea, dizziness, tinnitus (quinidine “Cinchonism”)

5.Pharmacokinetics/therapeutics

a.Oral, rapidly absorbed, 80% bound to membrane proteins

b.Hydroxylated in liver; T1/2 = 6-8 h

c.Drug interaction: displaces digoxin from binding sites

d.Some active metabolites of quinidine

e.Effective in treatment of nearly all dysrhythmias, including:

1)Premature atrial contractions

2)Paroxysmal atrial fibrillation and flutter

3)Intra-atrial and A-V nodal reentrant dysrhythmias

4)Wolff-Parkinson-White tachycardias (short PR, long QRS)

5)PVCs, nonsustained VTs

f.Useful in chronic dysrhythmias requiring outpatient treatment

B.Procainamide (Class 1A)

1.Cardiac effects

aVery similar to quinidine in general but less blockade of muscarinic and adrenergic receptors.

b.Has negative inotropic action

2.Extracardiac effects

a.Ganglionic blocking reduces peripheral vascular resistance

3.Toxicity

a.Cardiac: Similar to quinidine; cardiac depression

b.Syndrome resembling lupus erythematosus (inflammatory disease, reversible, significiant with long-term therapy)

4.Pharmacokinetics/therapeutics

a.Administered orally, I-V

b.Major liver metabolite is N-acetylprocainamide (NAPA), a weak Na+ channel blocker with class III activity. Bimodal distribution in population of rapid acetylators, accumulate high levels of NAPA.

c.T1/2 = 3-4 hours; necessitates frequent dosing; kidney chief elimination path. NAPA has longer T1/2 and accumulates readily.

d.Usually used short-term.

C.Lidocaine (Class IB prototype; other Phenytoin, Tocainide, Mexiletine)

a.Use as antidysrhythmic agent in emergency care (AHA 2001) decreased

b.Given I-V; commonly used in ICU (old DOC; “Drug of Choice”).

c.Very low toxicity, good therapeutic index

d.A local anesthetic, works on nerve at higher doses.

2.Cardiac effects

a.Generally decreases APD, hastens AP repolarization, decreases automaticity and increases refractory period in depolarized cells.

b.Exclusively acts on Na channels in depolarized tissue by blocking open and inactivated Na channels

c.Potent suppresser of abnormal activity

d.Most Na channels of normal cells rapidly unblock from lidocaine during diastole; few electrophysiological effects in normal tissue

3.Toxicity:- least cardiotoxic, high dose can lead to hypotension

- tremors, nausea, slurred speech, CNS stimulation & convulsions

4.Pharmacokinetics/therapy

  1. Usually given I-V, since extensive first pass hepatic metabolism
  2. T1/2 = 0.5-4 hours; rapid onset and short duration of action.
  3. Very effective in suppressing dysrhythmia associated with depolarized tissue (ischemia; digitalis toxicity); ineffective against dysrhythmias in normal tissue (atrial flutter).
  4. Suppresses ventricular dysrhythmias; prevents ventricular fibrillation after acute MI; rarely used in supraventricular arrythmias. But in recent years, antiarrythmic use has been limited.

D.Phenytoin (Class IB)

1.Non-sedative anticonvulsant used in treating epilepsy

2.Limited efficacy as antidysrhythmic (second line antiarrythmic)

3.Suppresses ectopic activation by blocking Na and Ca channels

4.Especially effective against digitalis-induced dysrhythmias

5.T1/2 = 24 hr - metabolized in liver

6.Use associated with gingival hyperplasia

E.Flecainide (Class IC prototype)
Other examples: Lorcainide, Propafenone , Indecainide, Moricizine. Depress rate of rise of AP without change in refractoriness or APD in normally polarized cells

  1. Decreases automaticity and conduction in depolarizedcells.
  2. Marked block of open Na channels (decreases Ph. 0); little or no change in repolarization.
  3. Relatively new compared to other antidysrhythmics
  4. Used primarily for ventricular dysrhythmias, but effective for atrial and supraventricular arrythmias, and prevention of atrial fibrillation/flutter.
  5. No antimuscarinic action
  6. Suppresses premature ventricular contractions
  7. Associated with significant mortality (CAST study); marked tendency to exacerbate or precipitate dysrhythmias. Thus, use limited to last resort applications like treating ventricular tachycardias.
  8. Significantly negative inotropic effect.

F.Propranolol (Class II, beta adrenoreceptor blockers; other examples: esmolol, sotalol, acebutolol; metoprolol (beta-1 blocker); or carvedilol (alpha- and beta-blocker).

- Beta blockers are now often the drugs of choice for rate control, along with Ca channel blockers for supraventricular tachycardias.

- Generally beta-blockers with partial agonist (ISA) ie Pindolol are not used

1.General properties of all Class II agents:

a.Slow A-V conduction

b.Prolong A-V refractory period

c.Suppress automaticity

2.Cardiac effects (of propranolol), a non-selective beta blocker

a.Main mechanism of action is block of beta receptors;  Ph 4 slope. which decreases automaticity under certain conditions

b.Some direct local anesthetic effect by block of Na channels (membrane stabilization)-at higher doses

c.Increases refractory period in depolarized tissues

d.Increases K channel current

e.Increases A-V nodal refractory period

3.Non-cardiac: Hypotension

4.Therapeutics

a.Blocks abnormal pacemakers in cells receiving excess catecholamines (e.g. pheochromocytoma) or having up-regulated betas (thyroid disorder)

b.Blocks A-V nodal reentrant tachycardias; inhibits ectopic foci

c.Beta-blockers are used to treat supraventricular tachydysrhythmias; objective to slow the ventricular rate by beta affects on A-V conduction rather than abolish dysrhythmias.

d.Propranolol is contraindicated in patients with ventricular failure; can lead to A-V block.

e.Oral (propranolol) or IV. Extensive metabolism in liver.

G.Amiodarone (Class III; others: Ibutilide, Bretylium, Sotalol, Dronedarone)

  1. General
  2. A Class III drug which prolongs refractory period by blocking potassium channels; structural analog of thyroid hormone which interacts with nuclear thyroid hormone receptors; very lipophilic.
  3. Also member of Classes IA, II, III, IV since blocks Na, K, Ca channels and alpha and beta adrenergic receptors
  4. Dronedarone (↓adverse effects?) similar to Amiodarone, approved Jul 2009.
  5. Among most widely used and effective dysrhythmic agents.
  1. Cardiac effects:
  2. Block Na channels, but low affinity for open channels; mainly blocks inactivated Na channels
  3. Block most pronounced in tissue with long APsor more depolarized diastolic potential
  4. Weak Ca channel blocker also (Class IV activity)
  5. A powerful inhibitor of abnormal automaticity, decreases conduction, increases refractory period and APD, increases QT interval
  6. Has antianginal effects (blocks alpha/beta receptors and Ca channels)
  7. Extracardiac effects: Vasodilation via block of Ca channels and alpha receptors
  8. Adverse Effects:
  9. Cardiac
  10. Sinus bradycardia
  11. Negative inotropic action due to block of Ca channels and beta receptors; but can improve heart failure via vasodilation.
  12. A-V block, paradoxical VTs., ↑QT interval
  13. Non-cardiac:
  14. Deposits into almost every organ
  15. Reduces clearance of drugs like procainamide, flecainide, digitalis, quinidine and diltiazem.
  16. Thyroid dysfunction (hypo or hyperthyroidism)
  17. Pulmonary fibrosis is most serious adverse effect
  18. Paresthesias(tingling, pricking, or numbness, “pins and needles”)
  19. Photosensitivity
  20. Corneal microdeposits and blurred vision
  21. Ataxia, dizziness, tremor
  22. Anorexia, nausea
  23. Pharmacokinetics and therapeutics
  24. T1/2 = 13-103 days (weeks) very long for one dose; very lipid soluble; metabolized in liver (Dronedarone 24 hrs)
  25. Effective against many arrythmias: atrial, A-V and ventricular dysrhythmias; prevention of atrial fibrillation/flutter; PVCs, nonsustained and sustained VTs.
  26. There exist multiple interactions with other drugs such as:

i. Amiodarone is a CYP3A4 substrateand inhibitor and thus may enhance the effect of other CYP3A4 substrates eg. Warfarin, Simvastatin, Verapamil

ii. Amiodarone may increase the serum concentration of Cardiac Glycosides

H.Bretylium (Class III, K channel blockers; others ibutilide)

1.General: originally used as an antihypertensive agent, availability limited

2.Cardiac effects

a.Direct antidysrhythmic action

b.Increases ventricular APD and increases refractory period; decreases automaticity

c.Most pronounced action in ischemic cells having short APD

d.Initially stimulates and then blocks neuronal catecholamine release from adrenergic nerve terminals

e.Blocks cardiac K channels to increased APD.

3.Extracardiac effects: Hypotension (from block of NE release)

4.Pharmacokinetics/therapeutics

a.IV or intramuscular

b.Excreted mainly by the kidney

c.Usually emergency use only: ventricular fibrillation when lidocaine and cardioversion therapy fail. Increases threshold for fibrillation.

d.Decreases tachycardias and early extrasystoles by increasing effective refractory period

I.Ibutilide (Class III). Prolongs cardiac action potential without additional effects.

  1. Mechanism incompletely understood but it known to increase inward Na current and decrease repolarizing K current in cardiac cells.
  2. Can be administered I-V.Most effective current agent to convert atrial fibrillation and flutter of recent onset to normal rhythm. Low incidence of Torsades (about 2%), compared to other drugs.
  3. More effective for flutter than fibrillation
  4. Generally well tolerated

J.Sotalol (Class III and Class II)

  1. Non-selective beta blocker, also increases action potential duration.
  2. Increases APD, ↑QT interval
  3. Used for dysrhythmias of supraventricular and ventricular origin

K.Verapamil (Class IV, Ca channel blockers; other eg. diltiazem)

1.Cardiac

a.Block active and inactivated L-type Ca channels, prevents Ca entry

b.More effective on depolarized tissue, tissue firing frequently or areas where activity dependent on Ca channels (SA node; A-V node)

c.Increases A-V conduction time and refractory period; directly slows SA and A-V node automaticity

d.suppresses oscillatory depolarizing after depolarizations due to digitalis

e.Note that dihydropyridine Ca channel blockers are poor antiarrythmics

2.Extracardiac

a.Peripheral vasodilatation via effect on smooth muscle

b.Used as antianginal, antihypertensive

c.Hypotension may increase HR reflexively.

3.Toxicity

  1. Cardiac
  2. Too negative inotropic for damaged heart, depresses contractility
  3. Can produce complete A-V block
  4. Extracardiac
  5. Hypotension
  6. Constipation
  7. Nervousness

4.Pharmacokinetics/Therapeutics

a.T1/2 = 7h

b.Metabolized by liver

  1. Oral administration; also available parenterally
  2. Great caution for patients with liver disease
  3. Blocks reentrant supraventricular tachycardia ("A-V nodal reentrant tachycardia"), decreases atrial flutter and fibrillation
  4. Only moderately effective against ventricular arrythmias
  5. Can inhibit oscillatory depolarizing afterdepolarizations due to digitalis toxicity
  1. Examples of antidysrhythmic agents that do not fit the Vaughan-Williams classification
  1. Adenosine
  2. Naturally occurring nucleoside which is often used in the field by rescue squads as well as in the hospital.
  3. Activates P1 purinergic receptors (subtype A1) coupled to cardiac K channels, especially in nodal tissue.
  4. Has sympatholytic action
  5. Given as IV bolus to quickly slow conduction in A-V node and increase A-V refractory period. Decreases the rate of discharge of pacemaker cells.
  6. Effective in slowing or abolishing A-V nodal dysrhythmias, may also produce a period of asystole.
  7. T1/2 very short, 15 seconds; rapid elimination of the drug
  8. Toxicity
  9. Flushing (due to vasodilation)
  10. Hypotension
  11. Shortness of breath or burning sensation in chest

  1. Potassium ions (K+)
  2. Depress ectopic pacemakers
  3. Can suppress hypokalemia-induced dysrhythmias
  4. Toxicity
  5. Cardiac
  6. Can depress conduction
  7. Can lead to reentrant dysrhythmias
  8. Digoxin
  9. Used to treat atrial flutter and fibrillation, since it slows ventricular responses by slowing A-V node conduction; vagomimetic. Digoxin can also itself produce VTs, which can be treated with digoxin antibodies (first line) or drugs such as phenytoin or lidocaine.
  10. Mg: Used to treat Torsades de pointes, plus overdrive pacing if needed.
  11. Autonomic agents: Beta-agonists (ie. Isoproterenol)), anticholinergics (Atropine), used to treat AV block
  1. Current Drugs of Choice for Treatment of Some Dysrhythmias (see also Figure IX. Dysrhythmics treatment summary:

This is a complex and advanced clinical issue and must be individualized to the patient and the situation