Procainamide hydrochloride is metabolized through the action of n-acetyltransferase. The product of enzymatic metabolism of procainamide hydrochloride is n-acetylpro-cainamide (NAPA), which possesses only 25% of the activity of the parent compound.26 A study of the disposition of procainamide hydrochloride showed that 50% of the drug was excreted unchanged in the urine, with 7% to 24% recovered as NAPA.28,29 Unlike quinidine, procainamide hydrochloride is bound only minimally to plasma proteins. Between 75% and 95% of the drug is absorbed from the gastrointestinal tract. Plasma levels appear 20 to 30 minutes after administration and peak in about 1 hour.30
Procainamide hydrochloride appears to have all of the electrophysiological effects of quinidine. It diminishes automaticity, decreases conduction velocity, and increases action potential duration and, thereby, the refractory period of myocardial tissue. Clinicians have favored the use of procainamide hydrochloride for ventricular tachycardias and quinidine for atrial arrhythmias, even though the two drugs are effective in either type of disorder.
Disopyramide Phosphate, USP. Disopyramide phosphate, a-[2(diisopropylamino)ethyl]-a-phenyl-2-pyridine-acetamide phosphate (Norpace), is an oral and intravenous class IA antiarrhythmic agent. It is quite similar to quinidine and procainamide in its electrophysiological properties, in that it decreases phase 4 diastolic depolarization, decreases conduction velocity, and has vagolytic properties.31 It is used clinically in the treatment of refractory, life-threatening ventricular tachyarrhythmias. Oral administration of the drug produces peak plasma levels within 2 hours. The drug is bound approximately 50% to plasma protein and has a halflife of 6.7 hours in humans. More than 50% is excreted unchanged in the urine. Therefore, patients with renal insufficiency should be monitored carefully for evidence of overdose. Disopyramide phosphate commonly exhibits side effects of dry mouth, constipation, urinary retention, and other cholinergic blocking actions because of its structural similarity to anticholinergic drugs.
Lidocaine Hydrochloride, USP. Lidocaine hydrochloride, 2-(diethylamino)-2',6'-acetoxylidide monohydrochloride (Xylocaine), was conceived as a derivative of gramine (3-dimethylaminomethylindole) and introduced as a local anesthetic. It is now being used intravenously as a standard parenteral agent for suppression of arrhythmias associated with acute myocardial infarction and cardiac surgery. It is the drug of choice for the parenteral treatment of premature ventricular contractions.
Lidocaine hydrochloride is a class IB antiarrhythmic agent with a different effect on the electrophysiological properties of myocardial cells from that of procainamide and quinidine. It binds with equal affinity to the active (A) and inactive (I) Na+ ion channels. It depresses diastolic depolarization and automaticity in the Purkinje fiber network and increases the functional refractory period relative to action potential duration, as do procainamide and quinidine. It differs from the latter two drugs, however, in that it does not decrease, and may even enhance, conduction velocity
and increase membrane responsiveness to stimulation. There are fewer data available on the subcellular mechanisms responsible for the antiarrhythmic actions of lidocaine than on the more established drug quinidine. It has been proposed that lidocaine has little effect on membrane cation exchange of the atria. Sodium ion entrance into ventricular cells during excitation is not influenced by lidocaine because it does not alter conduction velocity in this area. Lidocaine hydrochloride does depress Na+ influx during diastole, as do all other antiarrhythmic drugs, to diminish automaticity in myocardial tissue. It also alters membrane responsiveness in Purkinje fibers, allowing increased conduction velocity and ample membrane potential at the time of excitation.32
Lidocaine hydrochloride administration is limited to the parenteral route and is usually given intravenously, although adequate plasma levels are achieved after intramuscular injections. Lidocaine hydrochloride is not bound to any extent to plasma proteins and is concentrated in the tissues. It is metabolized rapidly by the liver (Fig. 19.12). The first step is deethylation with the formation of monoethylglycinexylidide, followed by hydrolysis of the amide.33 Metabolism is rapid, the half-life of a single injection ranging from 15 to 30 minutes. Lidocaine hydrochloride is a popular drug because of its rapid action and its relative freedom from toxic effects on the heart, especially in the absence of hepatic disease. Monoethylglycinexylidide, the initial metabolite of lidocaine, is an effective antiarrhythmic agent; its rapid hydrolysis by microsomal amidases, however, prevents its use in humans.
Precautions must be taken so that lidocaine hydrochlo-ride solutions containing epinephrine salts are not used as cardiac depressants. Such solutions are intended only for local anesthesia and are not used intravenously. The aqueous solutions without epinephrine may be autoclaved several times, if necessary.
Phenytoin Sodium, USP. Phenytoin sodium, 5,5-diphenyl-2,4-imidazolidinedione, 5,5-diphenylhydantoin, diphenyl-hydantoin sodium (Dilantin), has been used for decades in the control of grand mal types of epileptic seizure. It is structurally analogous to the barbiturates but does not possess their extensive sedative properties. The compound is available as the sodium salt. Solutions for par-enteral administration contain 40% propylene glycol and 10% alcohol to dissolve the sodium salt.
Phenytoin sodium's cardiovascular effects were uncovered during observation of toxic manifestations of the drug in patients being treated for seizure disorders. Phenytoin sodium was found to cause bradycardia, prolong the PR interval, and produce T-wave abnormalities on electrocardiograms. It is a class IB antiarrhythmic agent. Today, phenytoin sodium's greatest clinical use as an antiarrhyth-mic drug is in the treatment of digitalis-induced arrhyth-mias.34 Its action is similar to that of lidocaine. It depresses ventricular automaticity produced by digitalis, without adverse intraventricular conduction. Because it also reverses the prolongation of AV conduction by digitalis, phenytoin sodium is useful in supraventricular tachycardias caused by digitalis intoxication.
Phenytoin sodium is located in high amounts in the body tissues, especially fat and liver, leading to large gradients between the drug in tissues and the plasma concentrations. It is metabolized in the liver.
Mexiletine Hydrochloride. Mexiletine hydrochloride, 1-methyl-2-(2,6-xylyloxy)ethylamine hydrochloride (Mexitil) (pKa 8.4), is a class IB antiarrhythmic agent that is effective when given either intravenously or orally. It resembles lidocaine in possessing a xylyl moiety but otherwise is different chemically. Mexiletine hydrochloride is an ether and is not subject to the hydrolysis common to the amides lidocaine and tocainide. Its mean half-life on oral administration is approximately 10 hours.
Although not subject to hydrolysis, mexiletine hydrochloride is metabolized by oxidative and reductive processes in the liver. Its metabolites, p-hydroxymexiletine and hydroxymethylmexiletine, are not pharmacologically active as antiarrhythmic agents.35
Was this article helpful?
Did you ever think feeling angry and irritable could be a symptom of constipation? A horrible fullness and pressing sharp pains against the bladders can’t help but affect your mood. Sometimes you just want everyone to leave you alone and sleep to escape the pain. It is virtually impossible to be constipated and keep a sunny disposition. Follow the steps in this guide to alleviate constipation and lead a happier healthy life.