Anti-arrhythmic Drugs

Anti-arrhythemic Drugs

• Normal heart rhythm is generated & driven by the spontaneous
firing of pacemakers cells of the SA node (post. wall of the RA)
• These cells have an intrinsic firing rate of 100-110 depolarization / sec
• The intrinsic rate is under the control of ANS, (+ or -)
• At rest, the SA rate, (HR in sinus rhythm), 60-80 b/m below intrinsic firing rate).
• This reduced resting rhythm is due to vagal tone
• Efferent vagus nerve fibers innervating the SA node normally have a high level of activity under resting conditions.
• These nerves (Ach binds to M2 rec. on the SA nodal cells to cause the decrease in firing rate.
• The SA node is also innervated by sympathetic fibers AN (NE), binds principally to B1-in SA nodal cells. When the activity of sympathetic efferent nerves is increased, the SA node firing rate increases.
• Normally, there is a reciprocal relationship between the parasym (vagal) & sym influences acting on the SA node
In normal sinus rhythm:
• the impulses generated by the SA node travel through the atria and converge at the AV node where the speed of conduction is reduced to give the atria sufficient time to contract & empty their contents into the ventricles prior to ventricular contraction.
• Impulses from the AV node travel into the ventricles via the Bundle of His, and then branch into the left and right bundle branches, the terminal Purkinje fibers, and finally are conducted to the ventricular myocytes.
• Because of this spread of electrical activity from the atria to the ventricles, every atrial depolarization & contraction is normally followed by ventricular depolarization & contraction.
• Normally : one-to-one correspondence between atrial & ventricular depolarization & contraction.

Arrhythmias: classifies according to
1. Altered rate
2. Premature beats
3. Altered conduction.
Altered Rate:
• Normal resting HR (60-100 bpm).
• < 60 bpm (bradycardia)& >100 (tachycardia).
• There are subcategories of altered rate such as
1. Sinus tachycardia or bradycardia (determined by SA)
2. Atrial tachy or brady (by atrial pacemaker site)
3. Supraventricular tachy & ventricular tachy
• Atrial tachycardias (250-350 bpm (>200 bpm in ventricles) are called flutter, and can be either atrial or ventricular in origin.
• Fibrillation occurs (either atrial or ventricular) when the frequency is so high and irregular that the rate cannot be determined.
Premature Beats
• Sometimes a cell within the atria or ventricles that is not normally a pacemaker cell (called an ectopic foci) spontaneously fires off an action potential. When this occurs, it can cause what is called a premature beat. If this occurs in the atria the impulse will generally be conducted to the ventricles and produce an early depolarization and contraction of the atria and ventricles. If the premature beat originates from a ventricular ectopic foci, this will lead to an early depolarization and contraction in the ventricles without affecting the atrial rhythm.
Altered Conduction
• Delays in the conduction of electrical impulses within the heart produce abnormal electrical activation of the heart that are termed conduction defects.
• These most commonly occur at the AV node. Less severe conduction delays at the AV node will only delay the time it takes for the impulse to reach the ventricles (1st degree AV block).
• If AV nodal conduction is depressed sufficiently, only some of the impulses may be able to travel into the ventricles leading to a loss of the one-to-one correspondence between the atria and ventricles (2nd degree AV block).
• Conduction blocks can also occur in the ventricular bundle branches. These blocks do not normally alter the ventricular rhythm, although they will alter ventricular activation and ventricular mechanical function. Special types of partial conduction blocks, sometimes in conjunction with abnormal conduction pathways (e.g., Wolff-Parkinson-White syndrome), can lead to reentry pathways that produce tachycardia.







Types of Arrhythmias
Bradycardia
1. Sinus bradycardia: excessive vagal stimulation (during fainting) or because of damage to the SA node (damage caused by ischemia or disease).
2. Ventricular bradycardia as a result of AV block, slow rate (30-40 beats/min).
Tachycardia
1. Excessive sympathetic nerve stimulation of the SA node or high circulating levels of catecholamines (e.g., pheochromocytoma).
2. Exercise, for example, is physiologic and normal. However, sinus tachycardia at rest is not normal
3. Atrial (non-sinus) tachycardia can occur due to either an ectopic foci firing at a high frequency or to reentry mechanisms within the atria. Both of these mechanisms may be stimulated by ischemia or increased sympathetic activity
4. Global reentry, accessory pathways between the right atrium and right ventricle (Bundle of Kent) can cause Wolff-Parkinson-White syndrome.
5. ventricular and or atrial dilation occurs
Other causes for premature beat or conduction defect:
• Ischemia
• Infection
• Inflammation
• Degenerative changes
• Trauma
• Other causes
Therapeutic Use and Rationale
• The ultimate goal of antiarrhythmic drug therapy is to restore normal rhythm and conduction.
• When it is not possible to revert to normal sinus rhythm, drugs may be used to prevent more serious and possibly lethal arrhythmias from occurring.
Antiarrhythmic drugs are used to:
• ?or ?conduction velocity
• Alter the excitability of cardiac cells by changing the duration of the effective refractory period
• Suppress abnormal automaticity






Classes of Drugs
• Class I - Sodium-channel blockers
• Class II - Beta-blockers
• Class III - K-channel blockers
• Class IV - Ca-channel blockers
• Miscellaneous – adenosine
- Electrolyte supplement (Mg& K)
- Digitalis (cardiac glycosides)
- Atropine (muscarinic rec antag)
Class I - Na-channel blockers
• block the fast Na- channels that are responsible for the rapid depolarization (phase 0) of fast-response cardiac AP.
• Type of AP is found in non-nodal, cardiomyocytes (e.g., atrial and ventricular myocytes; purkinje tissue).
• Also leads to a decrease in the amplitude of the action potential.
• In contrast, nodal tissue AP (SA,AV) do not depend on fast Na-channels for depolarization; instead, phase 0 depolarization is carried by Ca- currents. Therefore, Na-channel blockers have no direct effect on nodal tissue, at least through the blockade of fast Na-channels.
• Decrease in conduction velocity in non-nodal tissue (atrial & ventricular muscle, purkinje conducting system). (negative dromotropy).
• (e.g., reentry mechanisms). By depressing abnormal conduction, reentry mechanisms can be interrupted.
• also alter the action potential duration (APD) and effective
refractory period (ERP)
• The effects on ERP are not directly related to Na-channel
blockade, but instead are related to drug actions on
K- channels in phase 3 repolarization of AP.

Suppress abnormal automaticity
Indirect vagal effects
o The direct effect of Class IA antiarrhythmic drugs on AP is significantly modified by their anticholinergic actions. Inhibiting vagal activity can lead to both an increase in SA rate & AV conduction,
o Although a IA drug may effectively depress atrial rate during flutter, it can lead to an increase in ventricular rate because of an increase in the number of impulses conducted through the AV node (Anti-Ch effect),
o Thereby requiring concomitant treatment with a BBs or CCBs to slow AV nodal conduction.
o These anticholinergic actions are most prominent at the SA & AV nodes because they are extensively innervated by vagal efferent nerves.
o Different drugs within the IA subclass differ in their anticholinergic actions .
Class IA: AF, flutter; SVT & VT
Quinidine* anticho(moderate) cinchonism (blurred vision, tinnitus, headache, psychosis); cramping & nausea; enhances digitalis toxicity
Procainamide anticho(weak) lupus-like synd 25-30%
Disopryamide anticho (strong) negative inotropic effect
Class IB: (VT)
Lidocaine* IV only; VT and PVCs good efficacy in isch myoc
Tocainide orally active lidocaine analog pulmonary fibrosis
Mexiletine orally active lidocaine analog good efficacy in isch myoca

Class IC: life-threatening (SVT) & (VT)
flecainide* SVT induce life-threatening VT
propafenone SVT & VT; ?b & CCBs can worsen HF
moricizine VT; IB activity

Side Effects
• The antichol. effects of IA
(tachycardia, dry mouth, urinary retention, blurred vision & constipation. Diarrhea, nausea, headache & dizziness are also common SE of many Class I drugs.
• Quinidine enhances digitalis toxicity, especially if hypokalemia is present. Quinidine, by delaying repolarization, can precipitate torsades de pointes (especially in with long-QT syndrome), a VT caused by after depolarizations.
Disopyramide
• contraindicated for patients with uncompensated HF because of its negative inotropic actions;
Propafenone
• depress inotropic.
IC compounds
• can cause increased risk of sudden death with a prior hx of MI or sustained ventricular arrhythmias.
Beta-blockers
• block the binding of NE & Epi to receptors.
• Inhibits normal symp effects
• Some are partially activate the receptor while preventing norepinephrine from binding to the receptor. These partial agonists therefore provide some "background" of sympathetic activity while preventing normal and enhanced sympathetic activity. These particular beta-blockers (partial agonists) are said to possess intrinsic sympathomimetic activity (ISA).
• Some BBs possess what is referred to as membrane stabilizing activity (MSA). This effect is similar to the membrane stabilizing activity of Na-channels blockers that represent Class I antiarrhythmics.
1. First generation BBs(non-selective, (?1) + (?2) .
2. Second generation BBs cardioselective relatively selective for ?1.
3. Third generation BBs that also possess vasodilator actions through blockade of vascular alpha-adrenoceptors.
BBs bind to b-adrenoceptors located in cardiac nodal tissue, the conducting system, & contracting myocytes.
The heart has both ?1 and ?2 adrenoceptors, although the predominant receptor type in number and function is ?1.
Mechanism
• B-receptors are coupled to a Gs-proteins, which activate adenylyl cyclase to form cAMP from ATP. Increased cAMP activates a cAMP-dependent protein kinase (PK-A) that phosphorylates L-type Ca-channels, which causes increased Ca entry into the cell.
BBs cause decreases in heart rate, contractility, conduction velocity, and relaxation rate.
These drugs have an even greater effect when there is elevated sympathetic activity.
BBs can attenuate these sympathetic effects and thereby decrease sinus rate, decrease conduction velocity (which can block reentry mechanisms), and inhibit aberrant pacemaker activity.
BBs also affect non-pacemaker action potentials by increasing action potential duration and the effective refractory period. This effect can play a major role in blocking arrhythmias caused by reentry.
K- channels blockers Class III antiarrhythmic
• K-channels are responsible for repolarizing slow-response AP in non SA tissue and SA ,AV.
• drugs bind to & block the K-channels that are responsible for phase 3 repolarization
• slows (delays) repolarization
• leads to an increase in action potential duration and an increase in the effective refractory period (ERP)






Class/Drug HTN Angina Arrhy MI CHF Comments
Non-selective ?1/?2
carteolol X ISA; long acting; also for glaucoma
carvedilol X X ?-blocking activity
labetalol X X ISA; ?-blocking activity
nadolol X X X X long acting
penbutolol X X ISA
pindolol X X ISA; MSA
propranolol X X X X MSA; prototypical beta-blocker
sotalol X several other significant mechanisms
timolol X X X X Primarily for glaucoma
?1-selective
acebutolol X X X ISA
atenolol X X X X
betaxolol X X X MSA
bisoprolol X X X
esmolol X X ultra short acting; intra or postoperative HTN
metoprolol X X X X X MSA
nebivolol X relatively selective vasodilating (NO release)
Drug Therapeutic Uses Comments
Amiodarone VT, includuing VF; AF and flutter very long h/f (25-60 days); Class I, II, III & IV actions & therefore decreases phase 4 slope and conduction velocity; potentially serious SE (pulmonary fibrosis; hypothyroidism)
Dronedarone AF (non-permanent) and flutter structurally related to amiodarone, but has a much smaller Vd & shorter elimination h/F (13-19 hr); Class I, II, III & IV actions; containdicated in severe or recently decompensated HF;
increased risk for severe liver injury & serious CVS adverse events in permanent AF & therefore, this drug should be used only in sinus rhythm with a hx of non-permanent AF
Bretylium life-threatening VT and VF IV only; initial sympathomimetic effect (norepinephrine release) followed by inhibition, which can lead to hypotension

Sotalol VT; atrial flutter and AF also has Class II activity
Ibutilide atrial flutter &AF slow inward Na+ activator, which delays repolarization; –inhibits Na+-channel inactivation, which increases ERP; IV only; can cause life-threatening VT
Dofetilide atrial flutter &AF very selective K+-channel blocker; can cause life-threatening ventricular arrhythmias

Side Effects and Contraindications
• All of these compounds, like Class I compounds, are proarrhythmic as well as being antiarrhythmic.
• Pulmonary fibrosis (usually reversible).
• Cardiac effects: AV block, sinus brady. and torsades de pointes.
• Corneal microdeposits & blurred vision.
• Photosensitivity.
• Bluish discoloration of skin due to iodine accumulation.
• Amiodarone can cause bradycardia and AV block, & therefore is CI with heart block, or SA node dysfX.
• Hyper- or hypo- thyroidism due to interference with conversion of T4 to T3.
• Neurological: ataxia, dizziness, tremor, peripheral neuropathy and myopathy.
• GIT intolerance –nausea, vomiting and anorexia.
• Serum levels of dig, diltiazem, and quinidine are ? with amiodarone use.
CCBs
• Vascular S. M relaxation (vasodilation)
• Decreased myocardial force generation (negative inotropy)
• Decreased HR (negative chronotropy)
• Decreased conduction velocity within the heart (negative dromotropy), particularly at the AV node.
1. Dihydropyridines
2. Amlodipine
3. Felodipine
4. Isradipine
5. Nicardipine
6. Nifedipine
7. Nimodipine
8. Nitrendipine
Non-dihydropyridines
• Verapamil (phenylalkylamine class), is relatively selective for the myocardium, & is less effective as a systemic vasodilator drug.
• very important role in treating angina (by reducing myocardial oxygen demand and reversing coronary vasospasm) and arrhythmias.
• Diltiazem (benzothiazepine class) is intermediate between verapamil & dihydropyridines in its selectivity for vascular Ca-channels. By having both cardiac depressant and vasodilator actions,
• Diltiazem is able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines.
Side Effects and Contraindications
• Dihydropyridine flushing, headache, excessive hypotension, edema & reflex tachycardia. The activation of sympathetic reflexes and lack of direct cardiac effects make dihydropyridines a less desirable choice for angina.
• Non-dihydropyridine CCBs can cause excessive bradycardia, impaired electrical conduction ( AVnodal block), & depressed contractility.
• Preexistent bradycardia, conduction defects, or HF caused by systolic dysfX should not be given CCBs, especially the cardiac selective, non-dihydropyridines. CCBs, especially non-dihydropyridines, should not be administered to patients being treated with BBs
Others
Adenosine:
• Naturally occurring nucleoside, but at high doses it decreases conduction velocity and prolongs the Ref period and ?automaticity in AV node.
• I.V. adenosine has become the drug of choice for abolishing SVT and is replacing verapamil in this regard. It has low toxicity, but causes flushing, chest pain and hypotension. It has an extremely short duration of action (15 seconds).
MAGNESIUM
• Used for patients with digitalis-induced arrhythmias who were hypomagnesemic
• Magnesium infusion has been found to have antiarrhythmic effects in some patients with normal serum magnesium levels (torsade de pointes ).
• The mechanisms are not known, but magnesium is recognized to influence Na+,K+ ATPase, sodium channels, certain potassium channels, and calcium channels.
• The usual dosage is 1 g (as sulfate) given intravenously over 20 minutes and repeated once if necessary