Quinidine is an alkaloid obtained from various species of Cinchona or its hybrids, from Remijia pedunculata, or from quinine. Quinidine is the dextrorotatory isomer of quinine .
Quinidine (Quinidex) was one of the first clinically used antiarrhythmic agents. Because of the high inci-dence of ventricular proarrhythmia associated with its use and numerous other equally efficacious agents, quinidine is now used sparingly. Quinidine shares all of the pharmacological properties of quinine, including an-timalarial, antipyretic, oxytocic, and skeletal muscle re-laxant actions.
Quinidine’s effect on the electrical properties of a par-ticular cardiac tissue depends on the extent of parasympathetic innervation, the level of parasympa-thetic tone, and the dose. The anticholinergic actions of quinidine predominate at lower plasma concentrations. Later, when steady-state therapeutic plasma concen-trations have been achieved, the drug’s direct electro-physiological actions predominate. The direct and indi-rect electrophysiological actions are summarized in Table 16.2.
The indirect effect of quinidine on the sinoatrial node is a result of the drug’s potential to exert an anti-cholinergic action resulting in a slight increase in heart rate. Higher concentrations of quinidine have a direct effect of depressing the rate of spontaneous diastolic depolarization.
Quinidine administration results in a dose-depen-dent depression of membrane responsiveness in atrial muscle fibers. The maximum rate of phase 0 depolariza-tion and the amplitude of phase 0 are depressed equally at all membrane potentials. Quinidine also decreases atrial muscle excitability in such a way that a larger cur-rent stimulus is needed for initiation of an active re-sponse. These actions of quinidine often are referred to as its local anesthetic properties.
Both the direct and indirect actions of quinidine are important in determining its ultimate effect on A-V conduction. The indirect (anticholinergic) properties of quinidine prevent both vagally mediated prolongation of the A-V node refractory period and depression of conduction velocity; these effects lead to enhancement of A-V transmission. Quinidine’s direct electrophysio-logical actions on the A-V node are to decrease con-duction velocity and increase the ERP.
Quinidine can depress the automaticity of ventricu-lar pacemakers by depressing the slope of phase 4 de-polarization. Depression of pacemakers in the His-Purkinje system is more pronounced than depression of sinoatrial node pacemaker cells.
Quinidine also prolongs repolarization in Purkinje fibers and ventricular muscle, increasing the duration of the action potential. As in atrial muscle, quinidine ad-ministration results in postrepolarization refractoriness, that is, an extension of refractoriness beyond the recov-ery of the resting membrane potential. The indirect (an-ticholinergic) properties of quinidine are not a factor in its actions on ventricular muscle and the His-Purkinje system.
Serum K+ concentrations have a major influence on the activity of quinidine on cardiac tissue. Low extracel-lular K+ concentrations antagonize the depressant ef-fects of quinidine on membrane responsiveness, whereas high extracellular K+ concentrations increase quinidine’s ability to depress membrane responsive-ness. This dependency may explain why hypokalemic patients are often unresponsive to the antiarrhythmic effects of quinidine and are prone to develop cardiac rhythm disorders.
At normal therapeutic plasma concentrations, quinidine prolongs the PR, the QRS, and the QT intervals. QRS and QT prolongations are more pronounced with quini-dine than with most other antiarrhythmic agents. The magnitude of these changes is related directly to the plasma quinidine concentration.
Although myocardial depression is not a problem in pa-tients with normal cardiac function, in patients with compromised myocardial function, quinidine may de-press cardiac contractility sufficiently to result in a de-crease in cardiac output, a significant rise in left ventric-ular end-diastolic pressure, and overt heart failure. Quinidine can relax vascular smooth muscle directly as well as indirectly by inhibition of α1-adrenoceptors. The depressant effects of quinidine on the cardiovascular system are most likely to occur after IV administration, and therefore, quinidine should not be employed rou-tinely in the emergency treatment of arrhythmias. Because of its potential to cause marked depression of myocardial contractility and to decrease peripheral vas-cular resistance, parenteral administration of quinidine is seldom indicated.
The pharmacokinetic characteristics of quinidine:
Oral bioavailability : Almost complete absorption
Onset of action : 1–3 hours
Peak response : 1–2 hours
Duration of action : 6–8 hours
Plasma half-life : 6 hours
Primary route of metabolism : Hepatic; active metabolite
Primary route of excretion: 10–50% renal (unchanged)
Therapeutic serum concentration: 2–4 μg /mL
Primary indications for the use of quinidine include (1) abolition of premature complexes that have an atrial, A-V junctional, or ventricular origin; (2) restoration of normal sinus rhythm in atrial flutter and atrial fibrilla-tion after controlling the ventricular rate with digitalis; (3) maintenance of normal sinus rhythm after electrical conversion of atrial arrhythmias; (4) prophylaxis against arrhythmias associated with electrical countershock; (5) termination of ventricular tachycardia; and (6) suppres-sion of repetitive tachycardia associated with Wolff-Parkinson-White (WPW) syndrome.
Although quinidine often is successful in producing normal sinus rhythm, its administration in the presence of a rapid atrial rate (flutter and possibly atrial fibrilla-tion) can lead to a further and dangerous increase in the ventricular rate secondary to inhibition of basal vagal tone upon the A-V node. For this reason, digitalis should be used before quinidine when one is attempting to convert atrial flutter or atrial fibrillation to normal si-nus rhythm.
The most common adverse effects associated with quinidine administration are diarrhea (35%), upper gastrointestinal distress (25%), and light-headedness (15%). Other relatively common adverse effects in-clude fatigue, palpitations, headache (each occurring with an incidence of 7%), anginalike pain, and rash. These adverse effects are generally dose related and re-versible with cessation of therapy. In some patients, quinidine administration may bring on thrombocytope-nia due to the formation of a plasma protein–quinidine complex that evokes a circulating antibody directed against the blood platelet. Although platelet counts re-turn to normal on cessation of therapy, administration of quinidine or quinine at a later date can cause the reappearance of thrombocytopenia.
The cardiac toxicity of quinidine includes A-V and intraventricular block, ventricular tachyarrhythmias, and depression of myocardial contractility. Ventricular arrhythmia induced by quinidine leading to a loss of consciousness has been referred to as quinidine syn-cope. This devastating side effect is more common in women than in men and may occur at therapeutic or subtherapeutic plasma concentrations.
Large doses of quinidine can produce a syndrome known as cinchonism, which is characterized by ringing in the ears, headache, nausea, visual disturbances or blurred vision, disturbed auditory acuity, and vertigo. Larger doses can produce confusion, delirium, hallucina-tions, or psychoses. Quinidine can decrease blood glucose concentrations, possibly by inducing insulin secretion.
One of the few absolute contraindications for quinidine is complete A-V block with an A-V pacemaker or id-ioventricular pacemaker; this may be suppressed by quinidine, leading to cardiac arrest.
Persons with congenital QT prolongation may de-velop torsades de pointes tachyarrhythmia and should not be exposed to quinidine.
Owing to the negative inotropic action of quinidine, it is contraindicated in congestive heart failure and hy-potension.Digitalis intoxication and hyperkalemia can accen-tuate the depression of conduction caused by quinidine.
Myasthenia gravis can be aggravated severely by quinidine’s actions at the neuromuscular junction.
The use of quinidine and quinine should be avoided in patients who previously showed evidence of quini-dine-induced thrombocytopenia.
Quinidine can increase the plasma concentrations of digoxin, which may in turn lead to signs and symptoms of digitalis toxicity. Gastrointestinal, central nervous system (CNS), or cardiac toxicity associated with elevated digoxin concentrations may occur. Quinidine and digoxin can be administered concurrently; however, a downward adjustment in the digoxin dose may be required.
Drugs that have been associated with elevations in quinidine concentrations include acetazolamide, the antacids magnesium hydroxide and calcium carbonate, and the H2-receptor antagonist cimetidine. Cimetidine inhibits the hepatic metabolism of quinidine. Phenytoin, rifampin, and barbiturates increase the hepatic metabo-lism of quinidine and reduce its plasma concentrations.
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