Table of Contents
Outline of the Pharmacological Treatment
The antiarrhythmic drugs are classified into categories by many classifications and among those, one of the most common and widely followed is the Vaughan-William Classification:
|Class 1||Fast sodium channel blockers. In turn, it is classified into three categories, namely:||1a — Quinidine, Disopyramide and Procainamide
1b — Mexiletine, Lidocaine and Phenytoin
1c — Moricizine, Flecainide, Propafenone
|Class 2||Antagonist at the beta channels – Beta blocker||Timolol, Propanolol, Esmolol, Metoprolol, and Atenolol|
|Class 3||Potassium channel blocker||Amiodarone Sotalol, Ibutilide and Dofetilide|
|Class 4||Slow calcium channel blockers||Verapamil and Diltiazem|
|Class 5||Miscellaneous drugs||Digoxin, Adenosine, Magnesium sulfate, Trimagnesium dicitrate|
Description of the Action Potential
The drugs which are described above can be better understood after gaining the knowledge of the action potential. The action potential of the heart can be divided into phases, with each channel being responsible for different phases. The action potential also varies between the different tissue of the heart, like the myocardium, the conduction tissue and the impulse center such as SA and AV node.
Here is the logical sequence in which the action potential occurs: First, it begins with the stimulus origin. When the stimulus exceeds the threshold, it leads to the depolarization. Then this is followed by the repolarization. There is also a refractory period, where even the occurrence of a stimulus will not elicit an action potential. This refractory period is in turn divided into relative and absolute refractory period.
Classification and Mechanism of Action
Miscellaneous antiarrhythmic agents include:
- Cardiac glycosides such as Digoxin
- Magnesium and potassium salts which constitute the electrolyte supplement
Digoxin forms the main member of the miscellaneous group, along with the Adenosine.
Mechanism of action
- It is used for two important conditions, namely
- When heart failure occurs due to the dysfunction in the systolic phase, and
- The supraventricular tachyarrhythmia
The usage of digoxin in both indications is superseded by the availability of better drugs.
Its mechanism of action in the case of supraventricular tachyarrhythmia is quite different when compared to that of heart failure. Digoxin causes direct suppression of the conduction through the AV node. This blockage increases the resistance for conduction of the impulse along the AV node.
This is important because whenever the supraventricular tachyarrhythmia occurs, the atrium is the first to suffer from tachyarrhythmia which then shifts to the ventricles. It is often the ventricular arrhythmia which is fatal to the patient. Thus, the refractory period and the conduction velocity decrease. There also occurs an increase in the vagal tone. The vagus generally plays an inhibitory role for the heart rate as against the sympathetic system.
In case of heart failure, digoxin inhibits the sodium/potassium ATPase pump in the cells of the myocardium. This is not the channel which is responsible for the calcium increase. Actually, the increase in calcium concentration is due to the activation of the sodium-calcium exchange pump. The inhibition of the sodium/potassium ATPase leads to an increase in the sodium concentration intracellularly, which, in turn, promotes the calcium influx via the sodium-calcium exchange pump. The ultimate increase in the intracellular calcium is the main reason why digoxin is efficient in heart failure.
Pros & Cons and the main indications
Digoxin is used in the treatment of atrial fibrillation, especially the chronic type with or without heart failure. It is also efficient with systole dysfunction, supraventricular tachyarrhythmia and heart failure.
Digoxin can be administered both intravenously and orally for control of the ventricular beat in atrial fibrillation. The intravenous route constitutes the rapid digitalization method and the oral dose constitutes the oral digitalization. There is also the concept of the initial loading dose followed by the maintenance dose.
In the case of atrial fibrillation, the loading dose of the intravenous route according to the AHA guidelines is 0.25 to 0.5 mg in short intervals, followed by a dose of 0.25 mg after six hours. The maintenance dose constitutes 0.25 mg once daily and is administered so that the drug will distribute well and hence remain efficacious in the long run. In patients suffering from renal failure, the dose needs to be adjusted appropriately.
Digoxin is mainly eliminated in the urine, with almost 80 % of it remaining unchanged.
In the case of atrial fibrillation which occurs following an increase in the sympathetic discharge, such as after exercise and in recurrent atrial fibrillation, this group of drugs is less effective when compared to the beta blockers and the calcium channel blockers. The drug is not very efficacious in controlling the symptoms in chronic resistant atrial fibrillation, in which case according to a Meta-analysis, amiodarone is better.
In addition to the decrease in efficacy, another important drawback with this group of medications is that the drug level needs to be monitored during the treatment, failure of which leads to digoxin toxicity.
This monitoring is required because the window of the therapeutic and toxic level of digoxin is very narrow. In a patient suffering from renal dysfunction, end stage renal disease or hypokalemia, further stringent monitoring of the digoxin level in the blood must be performed.
The recommended dose of digoxin is 0.5 to 0.8 ng/ml. It becomes toxic when the concentration increases to more than 2 ng/ml.
The most dangerous manifestation of digoxin toxicity is arrhythmia. Other presentations include disturbances in the gastrointestinal tract along with neurological signs such as confusion and weakness. Changes in the vision may also occur. Unfortunately, digoxin concentration does not always correlate with toxicity.
Treatment with the digoxin-specific antibody is recommended in all patients with clinically significant manifestation of digoxin toxicity. The other treatment option includes atropine which helps decrease the heart rate.
Patients with digitalis toxicity experience hyperkalemia, and administering the Fab fragment helps reduce potassium levels. Early recognition of digoxin toxicity and altering the medicine which affects the dose of digoxin is essential. In patients who experience toxicity following oral ingestion—and who present to the emergency department early—an initial treatment with activated charcoal will help remove any unabsorbed drug material.
The concentration of digoxin in the body increases with administration of Verapamil, Quinidine and Amiodarone. These medications have the propensity to cause digoxin toxicity. The antacids decrease the intestinal absorption and thus cause a decrease in the efficacy of the digoxin drug.
Adverse and side effects
In addition to toxicity, digoxin itself bears the risk of causing arrhythmias. Characteristic to digoxin side effects is the acceleration seen in the junctional rhythm along with the AV dissociation and ventricular tachycardia. There also is a risk of rashes, dizziness, apathy, disturbances in the mental thoughts. Gastrointestinal disturbances such as nausea, vomiting, diarrhea and pain in the abdomen may also occur.
Mechanism of action
Adenosine helps in the restoration of the normal sinus rhythm of the heart. This drug decreases the conduction along the AV node and also prevents the movement of the reentry circuits into the heart. The A1 receptor, along with the G0, is postulated to inhibit the calcium conductance which occurs in the conduction tissue.
Pros & cons and main indication
Adenosine is used in the treatment of Paroxysmal supraventricular tachycardia. The consensus is to start with an initial dose of 6 mg and then, if no response is detected, increase to a dose of 12 mg.
The drug is also used in diagnostic evaluation of myocardial perfusion scintigraphy, pharmacological stress testing and in testing of pulmonary artery hypertension for the acute vasodilator. This is because adenosine causes dilation only in the normal coronary artery without affecting the narrowed coronary artery. Thus the Thallium-201 radionuclides will be less absorbed in the narrowed coronary artery areas as compared to the normal coronary artery area.
The pharmacological stress test is the way of identifying those patients who are susceptible to angina development. When adenosine is administered, it causes stress, which potentiates the occurrence of angina (in a milder variety). With the development of better investigation methods and the employment of exercise stress testing, these pharmacological tests have been abandoned.
Adenosine has a peculiar metabolism. This drug is removed by the endothelial cells which line the vascular tissue. After uptake it is metabolized to AMP (Adenosine Monophosphate), which in turn, enters the energy pathway. Its ultimate elimination occurs via the uric acid pathway.
Drug efficacy is decreased by caffeine and theophylline products. Its toxic effect is enhanced via additional usage of carbamazepine, digoxin and dipyridamole.
Adverse and side effects
As with all antiarrhythmic drugs, there is always a risk of arrhythmias with adenosine administration. Other conditions that may occur include atrial premature contraction, atrial fibrillation and block. Additionally, there is an increased risk of facial flushing, headache, dizziness, disturbances of the gastrointestinal tract and dyspnea, as well as paresthesia, numbness and discomfort in the extremities.
Magnesium and Potassium Salts Which Constitute the Electrolyte Supplement
Indication and scope
In a patient with acute MI, the occurrence of hypokalemia and hypomagnesemia is a risk factor for ventricular arrhythmia. The incidence of ventricular arrhythmia increases twice in patients with hypokalemia. A Mg & K supplement mainly acts as a prophylaxis in preventing the occurrence of an arrhythmia in patients of MI. The successful correction of hypokalemia depends on the correction of hypomagnesemia. The ACC guidelines say that the magnesium level should be maintained above 2 mg/dl and the potassium level, above the 4 mg/ml.
Mechanism of action
There are two types of cholinergic receptors: muscarinic and nicotinic. The acetylcholine which is released from the vagal nerve ending is responsible for the deceleration of the heart, which in turn leads to bradycardia. Bradycardia is itself a significant risk factor for the occurrence of arrhythmia. Atropine acts as a competitive antagonist of acetylcholine at the level of the muscarinic receptors. No effect occurs in the nicotinic receptor.
Pros & Cons and main indication
Bradycardia is the off-label indication for which atropine is proposed to be beneficial. It has shown effect in one half of the patients with hemodynamically unstable bradycardia. In addition, this drug is also used to inhibit salivation, mushroom poisoning, neuromuscular blockade reversal and organophosphate poisoning.
Adverse and side effects
The side effects include all muscarinic receptor blocker side effects, such as dry mouth and gastrointestinal disturbances. They are reviewed in detail elsewhere.