Local anesthetics antiarrhythmic action

Caterall, W. A. Common modes of drug action on Na+ channels local anesthetics, antiarrhythmics and anticonvulsants, Trends Pharmacol. Sci. 1987, 8, 57-65. 

The Class I antiarrhythmic agents inactivate the fast sodium channel, thereby slowing the movement of Na" across the cell membrane (1,2). This is reflected as a decrease in the rate of development of phase 0 (upstroke) depolarization of the action potential (1,2). The Class I agents have potent local anesthetic effects. These compounds have been further subdivided into Classes lA, IB, and IC based on recovery time from blockade of sodium channels (11). Class IB agents have the shortest recovery times (t1 ) Class lA compounds have moderate recovery times (t 2 usually <9 s) and Class IC have the longest recovery times (t 2 usually >9 s). 

Glass IG Antiarrhythmic Agents. Class IC antiarrhythmic agents have marked local anesthetic effects. They slow the rapid inward sodium current producing marked phase 0 depression and slow conduction. Action potential duration of ventricular muscle is increased, ie, prolonged repolarization, but decreased in the His-Purkinie system by these agents. The effects on the ECG are increased PR interval, marked prolongation of the... 

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

Mechanism of action. Na -channel blocking antiarrhythmics resemble most local anesthetics in being cationic Liillmann, Color Atlas of Pharmacology... 

Pharmacology Propafenone is a Class 1C antiarrhythmic with local anesthetic effects and direct stabilizing action on myocardial membranes. 

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. 

Lidocaine hydrochloride Xylocaine) is the most commonly used local anesthetic. It is well tolerated, and in addition to its use in infiltration and regional nerve blocks, it is commonly used for spinal and topical anesthesia and as an antiarrhythmic agent (see Chapter 16). Lidocaine has a more rapidly occurring, more intense, and more prolonged duration of action than does procaine. 

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). 

Drugs with local anesthetic action block sodium channels and reduce the sodium current, INa. They are the oldest group of antiarrhythmic drugs and are still widely used. 

In some types of rhythm disorders, antiar-rhythmics of the local anesthetic, Na+-channel blocking type are used for both prophylaxis and therapy. These substances block the Na+ channel responsible for the fast depolarization of nerve and muscle tissues. Therefore, the elicitation of action potentials is impeded and impulse conduction is delayed. This effect may exert a favorable influence in some forms of arrhythmia, but can itself act arrhythmogenically. Unfortunately, antiarrhythmics of the local anesthetic, Na+-channel blocking type lack suf -cient specificity in two respects (1) other ion channels of cardiomyocytes, such as K1 and Ca+ channels, are also affected (abnormal QT prolongation) and (2) their action is not restricted to cardiac muscle tissue but also impacts on neural tissues and brain cells. Adverse effects on the heart include production of arrhythmias and lowering of heart rate, AV conduction, and systolic force. CNS side effects are manifested by vertigo, giddiness, disorientation, confusion, motor disturbances, etc. 

Mechanism of action. Na -channel blocking antiarrhythmics resemble most local anesthetics in being cationic amphiphilic molecules (p.206 exception phenytoin, p.191). Possible molecular mechanisms of their inhibitory effects are outlined on p.202 in more detail. Their low structural specificity is reflected by a low selectivity toward different cation channels. Besides the Na channel. Carotid 1C channels are also likely to be blocked. Accordingly, cationic amphiphilic antiarrhythmics affect both the depolarization and repolarization phases. Depending on the substance, AP duration can be increased (Class IA), decreased (Class IB), or remain the same (Class IC). Antiarrhythmics representative of these categories include Class IA—quinidine, procainamide, ajmaline, disopyramide Class IB—lidocaine, mexile-tine, tocainide Class IC—flecainide, propafenone. 

Propafenone is a class 1C antiarrhythmic drug with local anesthetic effects and a direct stabilizing action on myocardial membranes. The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (phase O) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by sodium ions. The diastolic excitability threshold is increased, and the effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity. 

Cardiovascular System Following systemic absorption, local anesthetics decrease electrical excitabdity, conduction rate, and force of contraction. Most local anesthetics also cause arteriolar dilation. Untoward cardiovascular effects usually are seen only after high systemic concentrations are attained and effects on the CNS are produced. However, on rare occasions, lower doses of some local anesthetics wUl cause cardiovascular collapse and death, probably due to either an action on the pacemaker or the sudden onset of ventricular fibrillation. Ventricular tachycardia and fibrillation are relatively uncommon consequences of local anesthetics other than bupivacaine. The use of local anesthetics as antiarrhythmic drugs is discussed in Chapter 34. Untoward cardiovascular effects of local anesthetic agents may result from their inadvertent intravascular administration, especially if epinephrine also is present. 

Amide-type local anesthetics (e.g., procainamide and lidocaine) also possess antiarrhythmic activity when given parenterally and at a subanesthetic dosage. Although this action can be attributed to their actions on sodium channels in cardiac tissues, current evidence suggests a distinctly different mechanism of action with respect to the modulation of channel receptors and the location of binding sites for these compounds (19,20). 

Lidocaine [2-(diethylamino)-N-(2, 6-dimethylphenyl) acetamide monohydrochloride] is the most commonly used amino amide-type local anesthetic. Lidocaine is very lipid soluble and, thus, has a more rapid onset and a longer duration of action than most amino ester-type local anesthetics, such as procaine and tetracaine. It can be administered parenterally (with or without epinephrine) or topically either by itself or in combination with prilocaine or etidocaine as a eutectic mixture that is very popular with pediatric patients. The use of lidocaine-epinephrine mixtures should be avoided, however, in areas with limited vascular supply to prevent tissue necrosis. Lidocaine also frequently is used as a class IB antiarrhythmic agent for the treatment of ventricular arrhythmias, both because it binds and inhibits sodium channels in the cardiac muscle and because of its longer duration of action than amino ester-type local anesthetics. 

They antagonize the positive inotropic and chronotropic effects of catecholamines. Cardiac arrhythmias associated with excessive adrenergic stimulus, released endogenous catecholamines or sensitization of the heart by anes-thetics or cardiac glycosides may effectively be treated by 6-blockade. Some B-blockers also possess membrane or local anesthetic action and are effective against arrhythmias due to ischemia or cardiac glycoside toxicity as well. This membrane action was shown to be independent of 6-blockade since resolved isomers of B-blockers possessed equal antiarrhythmic potency but unequal B-blocking action. 

The relationship between cardiac depressant, local anesthetic and 6-adrenergic blockade actions has evoked considerable interest. A common mechanism could be responsible for all actions. However, the separation of racemic alprenolol and propranolol into their optically active isomers resulted in only the levo isomers being potent 6-blockers while both isomers possessed local anesthetic and cardiac depressant actions . The separation of bunolol into its optical isomers resulted in a further separation of the actions of 6-blockers. Bunolol is devoid of significant antiarrhythmic and local anesthetic activities. Dextro-bunolol is inactive as a 6-blocker but did possess a cardio-depressant action equal to that of the leyo isomer. Thus, no correlation between local anesthetic, 6-blockade or toxic cardiac depression actions exist. Separate mechanisms for the three activities probably are involved. 

An analog (ICI 46037) structurally similar to propranolol was shown to possess local anesthetic and antiarrhythmic activity similar to propranolol in the dog. No -blocking action and a lower level of myocardial depressant action was observed . Other analogs have been reported recently having antiarrhythmic activity similar to quinidine in potency. These include 1,5-dimorpholino-3-(l-naphthyl)pentane (DA-1686) 2-propyl amino-1-naphthylpropane (S-931) ethoxamine (BW 62-235) and xipranolol (BS-79770)28. 

Local anesthetics are able to depress or block nerve conduction at low dosage Davis has demonstrated a relationship between antiarrhythmic potency, local anesthesia and neuromuscular transmission . The actions of antiarrhythmic agents to slow conduction can be explained by their depression of neuromuscular transmission. Slowed conduction can be explained through a retardation of the nerve impulse propagation, by increasing the electrical excitation threshold and reducing the rate of rise of the action potential . ... 

---