Cardiac Pharmacology: Anti-arrhythmia Drugs

Electrophysiology of the heart

There are 2 types of action potentials (AP) due to the presence of different ion channels:

Fast AP in the working myocytes & Purkinje fibers. The AP rises very fast and then assumes plateau, which is followed later by the repolarization. Lasts for ~0.3-1.4 ms.
This AP is characterized by overshooting to +40mV, no SDD, sudden upstroke & a plateau phase showing a very slow repolarization. The ion currents are showed by the membrane conductance (g):

Phase-0 → upstroke: activation of the fast voltage-gated Na⁺ channels, Na⁺ inflow, gNa⁺↑↑. During depolarization the K⁺ channels are closed → reaching Na⁺ equilibrium potential.

Phase-1 → initial peak: at the peak of depolarization the Na⁺ channels become inactivated until the membrane potential returns to normal, gNa⁺↓↓↓. Theres a small fast repolarization due to a delay in Ca²⁺ conductance.

Phase-2 plateau: theres an inflow of some Ca²⁺ & Na⁺ ions (gNa⁺ is a little higher than in resting potential). gCa²⁺ is elevated. The membrane potential decreases gradually by the positive ion flow. Under resting conditions gK⁺ >> gNa⁺ & gCa²⁺. After the upstroke theres a sudden drop in gK⁺. During plateau level, the gK⁺ increases very slowly. The plateau is caused by the K⁺ outflow, against Na⁺ & Ca²⁺ inflow.

Phase-3 → repolarization: caused by the increase in gK⁺. The K⁺ outflow is higher compared to the Na⁺ & Ca²⁺ inflow, since the Ca⁺² channels close at -30mV (voltage sensitive repolarization).

Phase-4 → resting potential: ~ -90mV, primarily K⁺ equilibrium potential (according to Nernst equation → 98mV) maintained by Na⁺/K⁺ pumps. When the original resting potential is restored, the gK⁺ is again higher than gNa⁺ & gCa²⁺.

To induce an upstroke in the cardiac muscle, we need a very small stimulus. During the first 2/3 of the plateau theres an absolute refractory period in which no additional AP can be generated (all Na⁺ channels are inactive). The critical value for stimulating an additional AP is ~ -40mV. The last 1/3 is the relative refractory period excitability gradually recovers; some Na⁺ channels are back to the resting, excitable state.

Threshold is reached by ↓↓ of K⁺ outflow permeability & ↑Na⁺ inflow.

Slow AP in the nodal conducting tissue. The rise is very slow, starting at 60mV without peaking, then starting to repolarize. Less negative & steep, with smaller amplitude (0.02-0.1ms):

• Phase-4 Spontaneous (slow) diastolic depolarization (SDD, pre-potential or pacemaker potential) the first part of the curve, with maximal resting potential of -60mV.
  Pacemaker cells have no fast Na⁺ channels. Some slow Na⁺ channels are responsible for the SDD, which is caused by the constant background inflow of Na⁺ ions and the gradual ↓of K⁺ permeability until a threshold at -45mV, followed by a sudden upstroke to a max of +5mV.
• T-type Ca⁺² channels (Transient type) also open at the SDD phase and close at the threshold, then the L-type Ca⁺² channels (Long-lasting) open and cause the upstroke (phase-0). They are the dominant channels. Ca²⁺ prolongs the AP and controls the force of contraction.
• During phases 1&2 the K⁺ channels reopen, K⁺ outflow after being closed at phase-0.
• Phase-3 → repolarization occurs due to the closing of L-Ca⁺² channels Ca²⁺ inflow.

The SA node frequency is ~100/min and the AV frequency is ~40/min. The AV cells need longer time to reach threshold, due to lower inflow rate of background Na⁺ ions. Before they reach threshold they receive the higher frequency impulse from the SA node, overriding them. To change the pacemaker rate → hyperpolarize the nodal cells → lower resting potential by opening K⁺ channels or by ACh action on M₂-receptors → bradycardia.
The slope of depolarization can be decreased by Na⁺ & Ca⁺² blockers. The AP does not change since the L-type Ca⁺² channels are not affected and open at a different phase.

Arrhythmia formation arrhythmias are based on:

Impulse generation problems including sinus brady & tachyarrhythmias. We dont treat such cases except for sick sinus syndrome. When arrhythmias begin at the atrial walls → atrial extra systoles (ES). When the AV node takes over → junctional extra systoles. Ventricular arrhythmias are based on depolarization, caused by ectopic impulses.

Impulse conduction problems including:

a.       Reentry based arrhythmia including atrial flutter, AF (micro-reentry) and SVPT (macro-reentry). It also includes WPW syndrome with an anterograde & retrograde pathways.

b.      Blocks based arrhythmia including:

Simple atrial blocks → changing atrial rhythm.

AV blocks → 1^st degree (prolongation of conduction time), 2^nd degree (Mobitz & Wenchebach, when some impulses fail to reach the ventricle) & 3^rd degree (AV dissociation). These are sometimes treated with atropine.

Tawara blocks (BBB) & hemiblocks → treated by a pacemaker.

Vaughan-Williams classification

I.        Na⁺ channel blockers divided to 3 subgroups:

a.       Group I/A these drugs bind the active, open Na⁺ channels (phase-0) and by that they slow the depolarization phase (↓ the AP slope). They have low affinity for the resting channels (phase-4) otherwise may cause cardiac arrest. To less degree they also bind inactive Na⁺ channels. The effect on the ECG → longer PQ segment.
I/A drugs reduce both the pacemaker rate and the supraventricular conduction speed → good for reentry based arrhythmias, but with a risk of AV block.
I/A also slightly block K⁺ channels → pro-arrhythmogenic effect with risk of early after depolarization since the relative refractory period is prolonged → VT (torsade de pointes).

b.      Group I/B very fast drugs, blocking mainly the inactive Na⁺ channels → have no effect on phase-0 of the AP, on the pacemaker rate, on the conduction and they dont change the repolarization (since they dont affect K⁺ channels). No effect on healthy myocytes.
I/B dissociate very fast → they bind at phase 2&3 and dissociate at phase-4.
In sick myocytes, the resting potential is closer to the threshold → easier to reach ES. So if we give I/B itll block the inactive Na⁺ channels thus block the next ES.
They inhibit the early stimulation during the SDD. An overdose is toxic and can kill.
Its given only for depolarization based ventricular arrhythmias → inhibit ectopic ventricular foci (arrhythmias from hypoxia, ischemic heart disease & digitalis intoxication).

c.       Group I/C the drugs with slowest binding & dissociation. They are very dangerous, since they strongly bind & block the open & inactive Na⁺ channels. These drugs are not used due to high mortality rate caused by the long lasting binding → very pro-arrhythmogenic.

II.         β-receptor blockers these reduce the heart rate (chrono~), conduction (dromo~) & contractility (inotropic). They are used for treating reentry-based & all the supraventricular tachyarrhythmias (AF, flutter, SVPT). The side effects include bradycardia, AV blocks and rarely even CHF (usually β-blockers are given for CHF).

III.       K⁺ channel blockers inhibitors of repolarization having also additional effects, otherwise they can kill. They are good for both ventricular & supraventricular tachyarrhythmias.
There are no pure group-III drugs, since all have other actions on other channels as well.

IV.      Ca⁺² channel blockers this group is also vasoactive ( vasodilation).
They reduce the pacemaker rate & conduction → good for supraventricular arrhythmias, such as AF, SVPT & for chronic use. They have limited side effects. Dont use in ventricular problems since they shorten the plateau.
Dihydropyridine drugs are only vasoactive, with no action on the heart → not group IV.

V.         Miscellaneous drugs not a real group, composed of totally different drugs.

I/A drugs (Na⁺ channel blockers)

Quinidine isomer of quinine with anti-malarial effect. Its an oral drug with all the actions of I/A → ↓pacemaker rate, conduction & slope of depolarization. It blocks K⁺ channels & prolongs repolarization → longer AP → QT prolongation on ECG.
Quinidine does not reduce the heart rate since it has a parasympatholytic action (muscarinic antagonist) → leading to tachycardia (↓Psy is accompanied with ↑Sym activity).
This effect though weaker than atropine, still overrides the main tendency of I/A to cause bradycardia and causes tachycardia instead. Giving digitalis before quinidine cardioversion will prevent the tachycardia. Quinidine cardioversion is used for AF or flutter → it slows the conduction speed and disrupts reentry circles, allowing the normal sinus impulse to pass through. The parasympatholytic action will take effect only after sinus rhythm has been reached, then causing tachycardia.
Since I/A also block K⁺ channels, the same as group-III → pro-arrhythmogenic side-effect, due to ↑ refractory period and risk of early after depolarization → torsade de pointes.
Quinidine is also an α-blocker → vasodilation, having the good effect of reducing afterload, but causing hypotension as well. Any vasodilation may result in reflex tachycardia.
Hyperkalemia will potentiate quinidine → arrhythmogenic.
Quinidine & digoxin → both compete for excretion sites→ quinidine may induce digitalis intoxication by ↑↑ its levels, not allowing it to be excreted.

o       Indications valid for all I/A drugs:

a.       Supraventricular & ventricular tachyarrhythmias → including reentry & conduction based arrhythmias. Restoring sinus rhythm from SVPT, AF & atrial flutter.

b.      Prophylaxis for AF → it can also be used chronically for prevention.

o       Dosage a wide range starting with a lower dose and then going up.
The initial dose is 3x200mg that may go up to 4x600mg (2.5g/day).

o       Side effects

a.       Tachycardia either due to vasodilation reflex or parasympatholytic action.

b.      Hypotension due to α-blocking activity.

c.       General effects nausea, vomiting, headache, dizziness & tinnitus.

d.      Allergic problems ranges from rashes to angioneurotic edema (Quinckes angioedema).

e.       Drug induced fever.

f.        Drug induced hepatitis.

g.       Torsade de pointes.

h.       Thrombocytopenia.

Procainamide similar to the local anesthetic procaine, (which has no anti-arrhythmic effect, since it dissolves too fast).
Procainamide is metabolized by the liver acetyl transferase to N-acetyl-procainamide, which has a pro-arrhythmogenic effect (→ torsade de pointes), due to strong K⁺ channels blockade, especially in fast acetylating people (some people are slow).
Procainamide has no parasympatholytic action but it has ggl. blocking effect, affecting mostly Sym ggl. → severe hypotension due to ↓↓ vasoconstriction.
Its never used chronically, since its toxic and can induce drug-induced lupus syndrome → arthritis, pericarditis, neuritis, etc. It was used by IV in acute cases but not used anymore.

Disopyramide (& imaline) metabolized & eliminated by the liver, unlike other I/A drugs. Its good for patients with renal problems that also have arrhythmia since it allows lower load on the damaged kidneys than other drugs.

I/B drugs (Na⁺ channel blockers)

Lidocaine a local anesthetic. It is a relatively safe drug with quite fast metabolism in the liver. The metabolites have no further action and are excreted through the kidney.
In case of ventricular arrhythmia → 100mg are given as a fast IV injection. Than a lidocaine infusion is given to maintain the level (500mg/min). its also good for digitalis intoxication.
Oral administration is not effective due to ↑ dose required. A very high dose will saturate the metabolic enzymes, reaching toxic drug levels → convulsions & cardiac arrest.
It binds only inactive Na⁺ channels.
It was indicted in the past following MI to prevent ventricular arrhythmias, but it cant prevent the MI complications → doesnt harm nor help, as found by recent studies.

Phenytoin a preventative anti-epileptic drug, which is sometimes used by IV for ventricular arrhythmias. It has 3 special indications:

a.       Digitalis intoxication.

b.      PVT.

c.       Congenital prolonged QT syndrome.

Mexiletine & tocainide similar to lidocaine, though more stable and can be used orally for chronic treatment.

Side effects include: tremor, blurred vision, lethargy & very rarely agranulocytosis.

I/C drugs (Na⁺ channel blockers)

Propafenone the only I/C drug used today, which has a β-blocking activity in addition to the active & inactive Na⁺ channel blockage.
The cardiac effects are similar to quinidine. It can even slow down pathological extra pathways (e.g. in WPW). It causes bradycardia and used to restore sinus rhythm after AF with no need of other medications (only anticoagulants).
It has an active metabolite → 5-OH propafenone, which is also anti-arrhythmic.

o       Indications:

a.       AV junctional tachycardia.

b.      Atrial tachyarrhythmias → AF & atrial flutter.

c.       Ventricular arrhythmias → but usually not used for such, due to the β-blocking effect.

o       Contraindications similar to β-blockers. Dont use in case of:

a.       CHF.

b.      Bradycardia.

c.       Different blocks.

d.      MI.

e.       Sick sinus syndrome.

f.        Myasthenia gravis.

o       Side effects partly β-blockers side effects:

a.       Nightmares.

b.      Confusion.

c.       Insomnia.

d.      Paresthesia.

e.       Visual problems.

Encainide & flecainide not used anymore due to ↑↑ mortality.

Group II drugs (β-blockers)

Propranolol & similar drugs are anti-arrhythmic due to β₁-blocking activity & direct membrane effects. Some drugs are selective for cardiac β₁-receptors (e.g. methoprolol), some have some intrinsic sympathomimetic action, some have direct membrane effect and some prolong the AP (the non-selective sotalol). These drugs are quite tolerated but are less efficient for suppressing ventricular ectopic foci than Na⁺ channel blockers but are very good to prevent recurrent MI & sudden death in people with acute MI. Esmolol is short acting for intraoperative use and acute arrhythmias.

They act against arrhythmias by ↑ the (-) chronotropic & dromotropic effects (↓pacemaker rate & slowing conduction). They are indicated for supraventricular tachyarrhythmias, essential tremor, hypertrophic CM, glaucoma, acute stress & pheochromocytoma.

Side effects:

Bradycardia & AV blocks.

Uterine contractions.

Cold hands & feet.

Hypoglycemia in insulin treated DM.

Nightmares.

Depression.

β-blockers specific for anti arrhythmia → we can use non selective drugs as propranolol, mainly in hyperthyroidism induced tachyarrhythmias. In case of sensitivity use nadolol or oxprenolol. Or use selective drugs as esmolol and methoprolol having a short activity.

Group III drugs (K⁺ channel blockers)

Inhibitors of repolarization (phase 3) → longer repolarization → prolonged AP. They can treat both ventricular & supraventricular arrhythmias. None of group-III has only 1 action → all have additional effects.

Amiodarone blocks K⁺, Na⁺ & Ca²⁺ channels and β-receptors. The K⁺ blocking is the most effective. It also blocks α-receptors → vasodilation & hypotension.
Can be given orally & parenterally.
Its indicated for ventricular & supraventricular tachyarrhythmias and ES. Its given for VF in emergency care units.
Oral administration is for chronic purposes, but the t½ of the drug differs from patient to patient can be 13 days or even 100 days we cant tell the maintenance dose that will be required later. IV injection though can treat acute cases. Side effects:

a.       Acute side effects bradycardia, AV blocks, CHF, hypotension and constipation.

b.      Chronic side effects very severe, involving iodine, which disturbs thyroid function. It mostly causes hypothyroidism but may cause hyperthyroidism.
Long term use can result in skin & corneal depositions, causing light sensitivity (photodermatitis) & disturbed vision (see yellow-brownish spots).
It may cause lung fibrosis, hepatocellular necrosis & liver adenomas.

Sotalol a β-receptor & K⁺ channel blocker. Its a mixture of enantiomers acting either on K⁺ channels or β-receptors. Sotalol has a regular t½ & metabolism of β-blockers. The long term side effects are not so severe with the same indications as amiodarone. When separating these stereoisomers, the K⁺ blocker alone is very dangerous → pro-arrhythmogenic (torsade de pointes).

Bretylium a noradrenergic neuroblocker. Since rapid tolerance develops to it, its only used in emergency cases as an anti arrhythmic K⁺ blocker. Bretylium is indicated for VT & VF. It uses for pharmacologic cardioversion, and if not helpful → apply electric shock.
Bretylium is a parenteral drug that cannot be used chronically, since it might cause hypotension.

Group IV drugs (Ca⁺² channel blockers)

Verapamil belongs to the phenylalkylamide group, having a cardiac & vasodilatatory action.

Diltiazem belongs to the benzodiazepine group, same effects as verapamil.

Dihydropyridine group not anti arrhythmic (not group-IV), causing vasodilation. They are given for hypertension & angina.

Verapamil & diltiazem have very similar actions in the heart → both block the slow L-type Ca⁺² channels. They reduce the plateau time so are contraindicated for ventricular arrhythmias, since in such cases the AP is shorter anyway and so is the diastole.
They slow the pacemaker rate & the AV conduction velocity. They cause bradycardia and block

reentry based arrhythmias (may cause AV blocks).

Indications for AF, atrial flutter & SVPT.
Verapamil can be used both chronically & acutely. Diltiazem is oral → for chronic use.

Dosage 5mg IV injection of verapamil can terminate SVPT, but can induce a transient asystole for a couple of seconds (a scary experience for the patient going from tachycardia to asystole to sinus rhythm).
The oral dose of verapamil is 3-4 x 80-100mg, much higher than IV, due to rapid liver metabolism.

Side effects considering long term they are safe, but may cause bradycardia & AV blocks. Verapamil must not be given together with β-blockers since they potentiate each other causing total AV dissociation (3^rd degree block). It also has a (-) inotropic effect and may cause constipation, by slowing the propulsive movements.
Diltiazem can cause the same effects but it may be combined with β-blockers, although due to similarity to verapamil and as a precaution, dont combine them.

Group V (miscellaneous drugs)

Digoxin & digitoxin have an anti-arrhythmic effect → for AF & atrial flutter.
They are given before quinidine cardioversion, to counteract the tachycardia caused by the parasympatholytic effect of quinidine.

Atropine indicated for AV blocks & bradycardia or to prevent bradycardia, which can be induced by halothane, a general anesthetic.

Edrophonium a short acting choline esterase inhibitor → ↑ACh action in the periphery.
It has a parasympathomimetic action on the atria → slows the pacemaker & AV node conduction, causing bradycardia. Its active only for a couple of minutes.
Side effects: abdominal pain, diarrhea, cramps, muscle weakness (since its antagonist for muscle relaxants, such as curare).

Adenosine it opens K⁺ channels and causes hyperpolarization of the atrial membranes.
Its active for ~10 sec when given by IV injection. Indicated for SVPT.

Some ions e.g.:

a.       K⁺ have anti-arrhythmic activity, mainly in case of hypokalemia.

b.      Mg²⁺ can be used as anti-arrhythmic, mainly in case of digitalis intoxication. Since it antagonizes digitalis, it can be used also in hypokalemia. Its also indicated in MI due to protective & preventive actions against some MI arrhythmic complications.
Its also reduces uterine contractility, a routine during pregnancy even without contractions by an infusion in order to prevent premature labor. Mg⁺² affects Na⁺, Ca⁺² & K⁺ channels dont know how. It also affects Na⁺/K⁺ ATPase, which is required for the normal function.