Why Does Lidocaine not Reduce the Incidence of Sudden Cardiac Death in Humans - Assignment Example

Theoretical basis for lidocaine’s presumed selectivity for the ischemic myocardium. Why does lidocaine not reduce the incidence of sudden cardiac death in humans? It is a well known fact that prolonged ischemia is the reason behind heart damage. Further on reperfusion of the heart with blood will cause severe damage to the heart (Lang et al, 1974). There is evidence to the fact that most heart damage occurring as a result would be due to the functional impairment of the mitochondria as well as the disruption of the cell membrane integrity (Jennings et al, 1978). This is usually known as the failure of function and progressive loss of ultra-structure (Buckberg et al, 1975). This ultra-structure damage includes the swelling of mitochondria, depletion of glycogen stores and modification of contractile elements (Schaper et al, 1975). Over the years several attempts have been made to reduce ischemic damage. Experiments with techniques such as Hypothermia as well as perfusing the coronary arteries with cold blood and glucocorticoids have been conducted without any significant results (Btusuittil et al, 1975). Recently however experiments with Lidocaine have opened up the possibilities of reducing ischemic damage to the heart. Lidocaine is a tertiary amine and classified as a Class I antiarrhythmic drug. It has been used for over 60 years as an important anesthetic. It has also been widely used to treat ventricular arrhythmias. Class I antiarrhythmic drugs work by blocking Na- channels. They function by means of dependence. This feature enables them to form variable affinities based on the different physical conformations of a channel. They are subdivided into three classes Ia, Ib and Ic. These categories are based on the selectivity of the drug for sodium versus potassium and their over all binding characteristics (Farkas and Curtis, 2002). The voltage gated Na-channels are held widely responsible to produce excitability in cardiac muscle as well as other important tissues. Therefore it is not surprising that they are the target of many antiarrhythmic, anticonvulsant as well as antimyotonic drugs (Catterall, 2002). It is thus for this reason that the state of the Na channels is determined largely by their voltage sensors and thus largely affect the affinity of a drug binding to the channel (Hille, 1977). The over all action of Lidocaine remains ambiguous but it is thought that the drug binds to the pore of the Na channel. Several mutagenesis experiments have shown that the drug binding is negligible if the pore of the Na channel is altered (Doyle et al, 1998). Recent studies however indicate that Lidocaine stabilizes (Seeman, 1972) the membrane and therefore helps in protecting the myocardium from ischemic damage (Schaub et al, 1977). Hence the infract size can be reduce by the administration of Lidocaine. Changes in the ability of anesthetic to bind with the sodium channels can be directly measured by measuring gating currents (Ig), these are minute electrical signals that result from the movement of the channels voltage sensors that are formed by the channels trans-membrane segments (S4) in all of the four domains of the channel (Bezanilla, 2000). The ventricular myocytes chick has been one of the first to be of observed for the reduction of the gating charge by Lidocaine (Josephson and Cui, 1994). Other observations have included cardiac purkinjee cells of dogs, Na channels of HEK293 cells of the human heart (Hanck et al., 2000), Na channels of the giant squid (Bekkers et al., 1984), Node of Ranvier of frog (Guselnikova et al., 1979) etc. Lidocaine thus shortens action potential. This is explained in two ways. Firstly it can occur due to an increased K conductance as explained by Bigger and Mandel (1970) or by a reduction of in-ward current (Mc-Allister et al., 1975). Lidocaine blocks the fast Na current, it is therefore thought that Lidocaine’s success in reducing action potential is due to the reduction of inward current (Weld and Bigger, 1975). Investigators like Sheet and Hanck (2003) focused heavily on the S4 segments in domains III and IV, as they had earlier determined that Lidocaine had blocked the movement of Na through domain III and IV but not domain I and II. They determined this by creating cystine residue mutations on several points in the S4 segment of the channel along with mutation of biotinoylaminoethylmethanethiosulphonate (MTSEA-biotin). This locked the segment in a state of depolarization and thus helped determine that if the position of the S$ segment was necessary for the high affinity of Lidocaine on the channel. Removal of the channels ability of fast inactivation via cystine mutation though greatly reduced Lidocaine’s ability to reduce to completely block Sodium currents but did not compromise its capability to reduce gating current of the channel. This is in part thought to be due to its capability to stabilize the S4 segment of the Na-channel. However, locking only the S4 segments of domain III and IV was seen to superiorly enhance the affinity of Lidocaine for the sodium channel. This implies that fro the successful action of Lidocaine the positioning of the S4 segment is very important. Lidocaine thus is known to exert positive effect on the ischemic heart. In an experiment by Okamura et al; (1982) it was observed that the left coronary blood flow was increased after reperfusion and exposure to Lidocaine. The drug was shown to be thus very effective in treating left ventricular fibrillation. It has been observed to be much more affective in preserving myocardial energy stores especially in conditions of ischemia and greatly decrease the chances of ischemic damage during early reperfusion and diminishes the possibilities of a patient developing myocardial edema. These benefits are often considered independent of the changes that are produced in coronary blood flow and left ventricular function. Although as mentioned earlier that many investigations have been carried out to protect the ischemic myocardium, many other pharmacological agents such as the β-blockers, Ca antagonists, glucocorticoids, aprotinin, hyalaurindse and local anesthetics have been emphasized with respect to increasing the chances of preserving the ischemic myocardium. Lidocaine thus is important in preventing the rapid loss of energy stores of the cell in the form of ATP and CP which other wise would lead to increase in sub-cellular and cellular membrane permeability. It is these changes in permeability that are largely responsible for movement of potassium out of the cell and the massive influx of sodium inside the cell. Changes in the conformation of the myocardial membrane affect the lipid bi-layer which is interspersed with proteins. These disruptions compromise the integrity of the membrane. Though other drugs such as procaine may help stabilize the membrane, Lidocaine tends to stabilize the membrane by inhibiting potassium influx three times more strongly than other drugs of its genre. Another investigation by Seppala and colleges have shown that Lidocaine in the mitochondrial membrane resists action of Phospholipase A, an enzyme released by the lysozome, which when activated will cause the further activation of destabilizing agents such as the unesterified fatty acids and lysophospholipids. With every drug come its limitations though Lidocaine has many success it cannot as such completely limit the occurrence of sudden cardiac death. Sudden cardiac is usually caused by the inability of the heart to perform. Though Lidocaine can help prevent damage of a newly re-perfused heart it cannot jump start a heart i.e. it cannot restore the complete capability of the heart’s channels to perform. Neither can it bring back the already damaged or deteriorating heart tissue. Once a membrane is destroyed beyond repair there are very few options left for the body to cope up with the stress of the damage and with Lidocaine only acting on the tiny membrane channels its ability is somewhat rendered limited in treating the heart. It may there for assist in recuperation of the heart but cannot therefore prevent incoming permanent damage. References Lang T, Corday E, Gold H, Meerbaum S, Rubins S, Constantini C, Hirose S, Osher J, Rosen V: Consequenses of repurfusion after coronary occlusion. Am J Cardiol 33:69, 1974 Jennings RB, Hawkins HK, Lowe JE, Hill ML, Klotman S, Reimer KA: Relation between high energy phosphate and lethal injury in myocardial ischemia in dog. Am J Pathol 92:187, 1978 Buckberg GD, Olinger GN, Mulder DG, Maloney JV: Depressed postoperative cardiac performance: Prevention by adequate myocardial protection during cardiopulmonary bypass. J Thorac Cardiovasc Surg 70:974-988, 1975 Schaper J, Hehrlein F, Thiedemann KU, Schlepper W: Ultrastructure of human myocardium after total cardiopulmonary bypass during open heart surgery. Recent Adv Stud Cardiac Struct Metab 6:399-404, 1975 Btusuittil RW, George WJ, Hewitt RL: Protective effect of methylprednisolone on the heart during ischemic arrest. J Thorac Cardiovasc Surg 70:995-965, 1975 Farkas A, Curtis MJ, (2002) Limited Antifibrillatory Effectiveness of Clinically Relevant Concentrations of Class I Antiarrhythmics in Isolated Perfused Rat Hearts Journal of cardiovascular Pharmacology™ 39:412–424 Catterall, W.A. 2000. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron. 26:13–25. Doyle, D.A., J.M. Cabral, R.A. Pfuetzner, A. Kuo, J.M. Gulbis, S.L. Cohen, B.T. Chait, and R. MacKinnon. 1998. The structure of the potassium channel: molecular basis of K_ conduction and selectivity. Science. 280:69–77. Hille, B. 1977. Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor reaction. J. Gen. Physiol. 69:497–515. Seeman P: The membrane actions of anesthetics and tranquilizers. Pharmacol Rev 24:583, 1972 Schaub RG, Lemole GM, Pinder GC, Black P, Stewart GJ: Effect of lidocaine and epinephrine on myocardial preservation following cardiopulmonary bypass in dog. Throc Cardiovasc Surg 74:571, 1977 Bezanilla, F. 2000. The voltage sensor in voltage-dependent ion channels. Physiol. Rev. 80:555–592. Bekkers, J.M., N.G. Greeff, R.D. Keynes, and B. Neumcke. 1984. The effect of local anaesthetics on the components of the asymmetry current in the squid giant axon. J. Physiol. 352:653–668. Guselnikova, G., E. Peganov, and B. Khodorov. 1979. Blockade of the gating currents in node of Ranvier under the action of the quaternary derivative of lidocaine (compound QX572). Dokl. Akad. Nauk SSSR. 244:1492–1494. Okamura, 1982 Seppala AJ, Saris NE, Gauffin ML: Inhibition of Phospholipase A-induced swelling of mitochondria by local anesthetics and related agents. Biochem Pharmacol 20:305, 1971 McAllister RE, Noble D, Tsien RW (1975) Reconstruction of the electrical activity of cardiac Purkinje fibres. J Physiol (Lond) 251: 1-59 Bigger JT, Mandel WJ (1970) Effect of lidocaine on the electrophysiological properties of ventricular muscle and Purkinje fibers. J Clin Invest 49: 63-77 Weld FM, Bigger JT (1975) Effect of lidocaine on the early inward transient current in sheep cardiac Purkinje fibers. Cir Res 37: 630-639 Sheets MF & Hanck DA (2003). J Gen Physiol 121, 163–175. Sheets MF & Hanck DA (2007). J Physiol 582, 317–334. Read More