Antiarrhythmic effects

The properties of -adrenoceptor blockers that contribute to antiarrhythmic effects are antagonism of neural/humoral P-adrenergic activity, and antagonism of catecholamine-mediated electrophysiological properties, ie, increase refractory period and decrease in the rate of diastoHc depolarization, ie, decrease automaticity and slow atrioventricular conduction (1,2). 

Ca2+ is an important intracellular second messenger that controls cellular functions including muscle contraction in smooth and cardiac muscle. Ca2+ channel blockers inhibit depolarization-induced Ca2+ entry into muscle cells in the cardiovascular system causing a decrease in blood pressure, decreased cardiac contractility, and antiarrhythmic effects. Therefore, these drugs are used clinically to treat hypertension, myocardial ischemia, and cardiac arrhythmias. 

Dantrolene is the mainstay of MH treatment. It has long been available for the treatment of muscle spasm in cerebral palsy and similar diseases. It is a hydantoin derivative that was first synthesized in 1967, and reported to be effective in the treatment of porcine MH in 1975. Also in 1975, dantrolene was shown to be more effective than procainamide in the treatment of human MH, which until that time was the drug of choice. However, the intravenous preparation was not made available until November 1979. It significantly lowered mortality. The half-life of dantrolene is estimated to be 6-8 hr. Dantrolene s primary mode of action is the reduction in calcium release by the sarcoplasmic reticulum. Dantrolene also exerts a primary antiarrhythmic effect by increasing atrial and ventricular refractory periods. Side effects of dentrolene include hepatotoxicity, muscle weakness, ataxia, blurred vision, slurred speech, nausea, and vomiting. Dantrolene is not contraindicated in pregnancy, but it does cross into breast milk and its effect on the neonate is unknown. 

Increased CNS depressant effects Increased effect of amphetamines Delusions, hostility Excessive anticholinergic effects Increased antiarrhythmic effect Decreased antihypertensive efficacy Acute organic brain syndrome... 

Schwartz, M.L., Meyer, M.B., Covino, B.G. and Narang, R.M. (1974). Antiarrhythmic effectiveness of intramuscular lidocaine Influence of different injection sites. J. Clin. Pharmacol. 14 77-83. 

Quinidine (6) and quinine (7) are diastereomeric quinoline alkaloids obtained from Cinchona spp. Quinidine (6) is included in many pharmacopeias for its antiarrhythmic effects.Quinine was the first antimalarial drug and served as an effective remedy for this deadly infectious disease in colonial times, making European settlement in many tropical and subtropical parts of the world possible.Owing to the development of resistance to synthetic antimalarials, quinine is still reverted to some extent for this... 

Alternatively, a loading infusion containing 20 mg/mL (1 g diluted to 50 ml with 5% dextrose injection, USP) may be administered at a constant rate of 1 mL/min for 25 to 30 minutes to deliver 500 to 600 mg. Some effects may be seen after infusion of the first 100 or 200 mg it is unusual to require more than 600 mg to achieve satisfactory antiarrhythmic effects. 

IV bolus - IV bolus is used to establish rapid therapeutic blood levels. Continuous IV infusion is necessary to maintain antiarrhythmic effects. The usual dose is 50 to 100 mg, given at a rate of 25 to 50 mg/min. If the initial injection does not produce the desired clinical response, give a second bolus dose after 5 minutes. Give no more than 200 to 300 mg/hour. 

Absorption/Distribution - Lidocaine is ineffective orally it is most commonly administered IV with an immediate onset (within minutes) and brief duration (10 to 20 minutes) of action following a bolus dose. Continuous IV infusion of lidocaine (1 to 4 mg/min) is necessary to maintain antiarrhythmic effects. Following IM administration, therapeutic serum levels are achieved in 5 to 15 minutes and may persist for up to 2 hours. Higher and more rapid serum levels are achieved by injection into the deltoid muscle. Therapeutic serum levels are 1.5 to 6 mcg/mL serum levels greater than 6 to 10 mcg/mL are usually toxic. Lidocaine is approximately 50% protein bound (concentration-dependent). 

Perform clinical and ECG evaluation as needed to determine whether the desired antiarrhythmic effect has been obtained and to guide titration and dose adjustment. Initial dose 200 mg every 8 hours when rapid control of arrhythmia is not essential, with a minimum of 2 to 3 days between adjustments. Adjust dose in 50 or 100 mg increments. 

Pharmacology Amiodarone possesses electrophysiologic characteristics of all 4 Vaughan Williams Classes but has predominantly Class III antiarrhythmic effects. The antiarrhythmic effect may be due to at least 2 major properties Prolongation of the myocardial cell-action potential duration and refractory period, and noncompetitive - and -adrenergic inhibition. 

Excretion - Following discontinuation of chronic oral therapy, amiodarone has a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 107 days. A much slower terminal plasma elimination phase shows a half-life of the parent compound of approximately 53 days. For the metabolite, mean plasma elimination half-life was approximately 61 days. Antiarrhythmic effects persist for weeks or months after the drug is discontinued. 

Serum concentrations have a major influence on the activity of quinidine on cardiac tissue. Low extracellular K+ concentrations antagonize the depressant effects of quinidine on membrane responsiveness, whereas high extracellular K+ concentrations increase quinidine s ability to depress membrane responsiveness. This dependency may explain why hypokalemic patients are often unresponsive to the antiarrhythmic effects of quinidine and are prone to develop cardiac rhythm disorders. 

Flecainide (Tambocor) is a fluorinated aromatic hydrocarbon examined initially for its local anesthetic action and subsequently found to have antiarrhythmic effects. Flecainide inhibits the sodium channel, leading to conduction slowing in all parts of the heart, but most notably in the His-Purkinje system and ventricular myocardium. It has relatively minor effects on repolarization. Flecainide also inhibits abnormal auto-maticity. 

Acebutolol is effective in the management of the patient with essential hypertension, angina pectoris, and ventricular arrhythmias. Antiarrhythmic effects are observed with the patient both at rest and taking exercise. 

Sotalol possesses a broad spectrum of antiarrhythmic effects in ventricular and supraventricular arrhythmias. It has value in the management of patients with paroxys-... 

There are no changes in the PR or QRS intervals, which reflects a lack of effect on the conduction velocity. Although there is no relationship between the plasma concentration of ibutilide and its antiarrhythmic effect, there is a dose-related prolongation of the QT interval. The maximum effect on the QT interval is a function of both the dose of ibutilide and the rate of infusion. 

Quinidine Similar class lA antiarrhythmic effect, leading to EKG parameter changes (e.g., longer QRS) Palpitations, bradycardia Need frequent monitoring of EKG parameters when drugs are used in combination Glassman and Preud homme, 1993... 

Bigger JT, Giardina EGV, Perel JM, et al. Cardiac antiarrhythmic effect of imipramine hydrochloride. N Engi J Med 1977 296 206-208. 

Giardina EGV, Bigger JT Jr, Glassman AH, et al. The electrocardiographic and antiarrhythmic effects of imipramine hydrochloride at therapeutic plasma concentrations. Circuiation 1979 60 1045-1052. 

Local anesthetic action, also known as "membrane-stabilizing" action, is a prominent effect of several 3 blockers (Table 10-2). This action is the result of typical local anesthetic blockade of sodium channels (see Chapter 26) and can be demonstrated experimentally in isolated neurons, heart muscle, and skeletal muscle membrane. However, it is unlikely that this effect is important after systemic administration of these drugs, since the concentration in plasma usually achieved by these routes is too low for the anesthetic effects to be evident. These membrane-stabilizing 3 blockers are not used topically on the eye, where local anesthesia of the cornea would be highly undesirable. Sotalol is a nonselective 3-receptor antagonist that lacks local anesthetic action but has marked class III antiarrhythmic effects, reflecting potassium channel blockade (see Chapter 14). 

In addition to their antianginal (see Chapter 12) and antiarrhythmic effects (see Chapter 14), calcium channel blockers also reduce peripheral resistance and blood pressure. The mechanism of action in hypertension (and, in part, in angina) is inhibition of calcium influx into arterial smooth muscle cells. 

These drugs, of which verapamil is the prototype, were first introduced as antianginal agents and are discussed in greater detail in Chapter 12. Verapamil and diltiazem also have antiarrhythmic effects. The dihydropyridines do not share antiarrhythmic efficacy and may precipitate arrhythmias. 

Dhein S, Schott M, Gottwald E, Tudyka T, Rutten P Antiarrhythmic effects of the antiarrhythmic peptide AAP10 in regional ischemia preservation of longitudinal propagation of activation. Circulation... 

Isolated heart Adrenergic nerves NA release (carrier-mediated) Ischemia-reperfusion arrhythmias inhibition antiarrhythmic effect Imamura et al., 1996a... 

Leifert WR, Jahangiri A, McMurchie EJ. Membrane fluidity changes are associated with the antiarrhythmic effects of docosahexaenoic acid in adult rat cardiomy-ocytes. J Nutr Biochem. 2000 I 1 38—44. 

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