Sodium channels cardiac

Clarkson CW, Hondeghem LM (1985) Mechanism for bupivacaine depression of cardiac conduction fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 62 396-405... 

In the Long QT Syndrome (LQTS), the repolarization phase of the cardiac muscle is delayed, rendering the heart vulnerable to an arrhythmia known as torsade de pointes. LQTS is associated with five genes encoding ion channels. LQTS type 3 (LQT3) results from mutations of Nav1.5, which cause persistent sodium cunent. In contrast, sodium channel mutations associated with Biugada syndrome reduce the expression level of cardiac sodium channels. 

The ion-channel blocking mechanism has been widely tested and found to be important in both pharmacology and physiology. Examples are the block of nerve and cardiac sodium channels by local anesthetics, or block of NMDA receptor channels by Mg2+ and the anesthetic ketamine. The channel-block mechanism was first used quantitatively to describe block of the squid axon K+ current by tetraethylammonium (TEA) ions. The effects of channel blockers on synaptic potentials and synaptic currents were investigated, particularly at the neuromuscular junction, and the development of the single-channel recording technique allowed channel blockages to be observed directly for the first time. 

It has been suggested that phenol exposure results in cardiac effects because it blocks the cardiac sodium channel subtype, with little effect on sodium channels in skeletal muscle (Zamponi et al. 1994). Phenol does not appear to be carcinogenic following oral exposure (NCI 1980), although the chemical combinations that result from benzene and phenol metabolism may contain compounds that do initiate or promote cancer. Metabolites such as hydroquinone and catechol have been demonstrated to be genotoxic and clastogenic. 

Zamponi GW, Ing D, French RJ. 1994. Arrhythmias during phenol therapies A specific action on cardiac sodium channels Circulation 89 914. 

Lidocaine is the most widely used local anesthetic. Its excellent therapeutic activity is fast-acting and lasts sufficiently long to make it suitable for practically any clinical use. It stabilizes cell membranes, blocks sodium channels, facilitates the secretion of potassium ions out of the cell, and speeds up the repolarization process in the cell membrane. It is used for terminal infiltration, block, epidural, and spinal anesthesia during operational interventions in dentistry, otolaryngology, obstetrics, and gynecology. It is also used for premature ventricular extrasystole and tachycardia, especially in the acute phase of cardiac infarction. Synonyms for this drug are xylocaine, neflurane, and many others. 

Ma, Y., Peters, N.S. and Henry, J.A. (2006) al-Acid glycoprotein reverses cocaine-induced sodium channel blockade in cardiac myocytes. Toxicology, 220, 46-50. 

Wang, Q., Shen, J.X., Li, Z.Z., Timothy, K Vincent, G.M., Priori, S.G., Schwartz, P.J. and Keating, M.T. (1995) Cardiac sodium-channel mutations in patients with long Qt syndrome. An inherited cardiac-arrhythmia. Human Molecular Genetics, 4, 1603—1607. 

The primary electrophysiological effects of moricizine relate to its inhibition of the fast inward sodium channel. Moricizine reduces the maximal upstroke of phase 0 and shortens the cardiac transmembrane action potential. The sodium channel blocking effect of moricizine is more significant at faster stimulation rates an action referred to as use dependence. This phenomenon may explain the efficacy of moricizine in suppressing rapid ectopic activity. An interesting effect of moricizine is its depressant effect on automaticity in ischemic... 

As with other members of class IB, mexiletine slows the maximal rate of depolarization of the cardiac membrane action potential and exerts a negligible effect on repolarization. Mexiletine demonstrates a rate-dependent blocking action on the sodium channel, with rapid onset and recovery kinetics suggesting that it may be more useful for the control of rapid as opposed to slow ventricular tachyarrhythmias. 

As with all members of its class, propafenone has its major effect on the fast inward sodium current. The IC agents depress over a wide range of heart rates and shift the resting membrane potential in the direction of hyperpolarization. The 1C agents bind slowly to the sodium channel and dissociate slowly. Therefore, they exhibit rate-dependent block. Inhibition of the sodium channel throughout the cardiac cycle will result in a decrease in the rate of ectopy and trigger ventricular tachycardia. 

Dofetilide s mechanism of action involves blockade of the cardiac ion channel that carries the rapid component of the delayed rectifier potassium current, IKr. Dofetilide inhibits IKr with no significant effects on other repolarizing potassium currents (e.g., IKs, IKl) over a wide range of concentrations. At plasma concentrations within the therapeutic range, dofetilide has no effect on sodium channels or on either i- or p-adreno-ceptors. 

Class I— membrane stabilizing drugs to reduce cardiac electrical excitability molecules that are sodium channel blockers, usually based on local anesthetic molecular structure... 

It is an alkaloid obtained from the bark of cinchona and is a dextro isomer of anti-malarial drug quinine. Its sodium channel blocking property results in an increased threshold for excitability and decreased automaticity. As a consequence of its potassium channel blocking properties, it prolongs action potential in most cardiac cells. 

Local anaesthetics directly depress myocardial conduction and contractility in a dose-dependent manner. They bind to and inactivate myocardial sodium channels, reducing the velocity of the cardiac action potential and prolonging the QRS interval. As plasma concentrations approach toxic values sodium channels become progressively inactivated until there is a generalised reduction in automaticity (cardiac slowing) with negative inotropy. Slow increases to near- or above-toxic levels are better tolerated than rapid rises seen following intravascular injection. 

Important differences between the available calcium channel blockers arise from the details of their interactions with cardiac ion channels and, as noted above, differences in their relative smooth muscle versus cardiac effects. Sodium channel block is modest with verapamil, and still less marked with diltiazem. It is negligible with nifedipine and other dihydropyridines. Verapamil and diltiazem interact kinetically with the calcium channel receptor in a different manner than the dihydropyridines they block tachycardias in calcium-dependent cells, eg, the atrioventricular node, more selectively than do the dihydropyridines. (See Chapter 14 for additional details.) On the other hand, the dihydropyridines appear to block smooth muscle calcium channels at concentrations below those required for significant cardiac effects they are therefore less depressant on the heart than verapamil or diltiazem. 

So-called bradycardic drugs, relatively selective If sodium channel blockers (eg, ivabradine), reduce cardiac rate by inhibiting the hyperpolarization-activated sodium channel in the sinoatrial node. No other significant hemodynamic effects have been reported. Ivabradine appears to reduce anginal attacks with an efficacy similar to that of calcium channel blockers and 3 blockers. The lack of effect on gastrointestinal and bronchial smooth muscle is an advantage of ivabradine, and FDA approval is expected. 

Most calcium channels become activated and inactivated in what appears to be the same way as sodium channels, but in the case of the most common type of cardiac calcium channel (the "L" type), the transitions occur more slowly and at more positive potentials. The action potential plateau (phases 1 and 2) reflects the turning off of most of the sodium current, the waxing and waning of calcium current, and the slow development of a repolarizing potassium current. 

Quinidine has actions similar to those of procainamide it slows the upstroke of the action potential and conduction, and prolongs the QRS duration of the ECG, by blockade of sodium channels. The drug also prolongs the action potential duration by blockade of several potassium channels. Its toxic cardiac effects include excessive QT interval prolongation and induction of torsade de pointes arrhythmia. Toxic concentrations of quinidine also produce excessive sodium channel blockade with slowed conduction throughout the heart. 

Propranolol 13- Adrenoceptor blockade Direct membrane effects (sodium channel block) and prolongation of action potential duration slows SA node automaticity and AV nodal conduction velocity Atrial arrhythmias and prevention of recurrent infarction and sudden death Oral, parenteral duration 4-6 h Toxicity Asthma, AV blockade, acute heart failure Interactions With other cardiac depressants and hypotensive drugs... 

Grant AO Molecular biology of sodium channels and their role in cardiac arrhythmias. Am J Med 2001 110 296. [PMID 11239848]... 

Splawski I et al Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 2002 297 1333. [PMID 12193783]... 

The excitable membrane of nerve axons, like the membrane of cardiac muscle (see Chapter 14) and neuronal cell bodies (see Chapter 21), maintains a resting transmembrane potential of -90 to -60 mV. During excitation, the sodium channels open, and a fast inward sodium current quickly depolarizes the membrane toward the sodium equilibrium potential (+40 mV). As a result of this depolarization process, the sodium channels close (inactivate) and potassium channels open. The outward flow of potassium repolarizes the membrane toward the potassium equilibrium potential (about -95 mV) repolarization returns the sodium channels to the rested state with a characteristic recovery time that determines the refractory period. The transmembrane ionic gradients are maintained by the sodium pump. These ionic fluxes are similar to, but simpler than, those in heart muscle, and local anesthetics have similar effects in both tissues. 

The cardiovascular effects of local anesthetics result in part from direct effects of these drugs on the cardiac and smooth muscle membranes and from indirect effects on the autonomic nervous system. As described in Chapter 14, local anesthetics block cardiac sodium channels and thus depress abnormal cardiac pacemaker activity, excitability, and conduction. At extremely high concentrations, local anesthetics can also block calcium channels. With the notable exception of cocaine, local anesthetics also depress myocardial contractility and produce direct arteriolar dilation, leading to systemic hypotension. Cardiovascular collapse is rare, but has been reported after large doses of bupivacaine and ropivacaine have been inadvertently administered into the intravascular space. 

It has been suggested that bupivacaine may be more cardiotoxic than other long-acting local anesthetics (eg, ropivacaine). This reflects the fact that bupivacaine-induced blockade of sodium channels is potentiated by the long action potential duration of cardiac cells compared with nerve fibers. The most common electrocardiographic finding in patients with bupivacaine intoxication is a slow idioventricular rhythm with broad QRS complexes and eventually electromechanical dissociation. 

Resuscitation from bupivacaine cardiovascular toxicity is extremely difficult even for experienced clinicians. Recent studies suggest that propofol can be useful in resuscitating patients acutely exposed to toxic levels of bupivacaine. The (S)-isomer, levobupivacaine, appears to have a lower propensity for cardiovascular toxicity than the racemic mixture or the (7 >isomer and has been approved for clinical use. The clinical effects of ropivacaine are similar to those of bupivacaine, but ropivacaine is allegedly associated with a lower potential for cardiovascular toxicity. Ropivacaine is available only as the ( SJ-stereoisomer, which has inherently less affinity for the cardiac sodium channel. However, both cardiac toxicity and CNS toxicity have been reported when large doses of ropivacaine were used for peripheral nerve blocks. 

In small doses, local anesthetics can depress posttetanic potentiation via a prejunctional neural effect. In large doses, local anesthetics can block neuromuscular transmission. With higher doses, local anesthetics block acetylcholine-induced muscle contractions as a result of blockade of the nicotinic receptor ion channels. Experimentally, similar effects can be demonstrated with sodium channel-blocking antiarrhythmic drugs such as quinidine. However, at the doses used for cardiac arrhythmias, this interaction is of little or no clinical significance. Higher concentrations of bupivacaine (0.75%) have been associated with cardiac arrhythmias independent of the muscle relaxant used. 

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