Sodium and potassium channels

There ate many classes of anticonvulsant agent in use, many associated with side effect HabiUties of unknown etiology. Despite many years of clinical use, the mechanism of action of many anticonvulsant dmgs, with the exception of the BZs, remains unclear and may reflect multiple effects on different systems, the summation of which results in the anticonvulsant activity. The pharmacophore stmctures involved are diverse and as of this writing there is htde evidence for a common mechanism of action. Some consensus is evolving, however, in regard to effects on sodium and potassium channels (16) to reduce CNS excitation owing to convulsive episodes. 

The Vaughan-Williams classification of antiarrhythmic drugs has been criticized for a number of reasons. The classification is based on the effects of drugs on normal, rather than diseased, myocardium. In addition, many of the drugs may be placed into more than one class. For example, the class IA drugs prolong repolarization/refractoriness, either via the parent drug8,9 or an active metabolite,10 and therefore also maybe placed in class III. Sotalol is also a 3-blocker, and therefore fits into class II. Amiodarone inhibits sodium and potassium channels, is a non-competitive inhibitor of 3-receptors, and inhibits calcium... 

Fig. 6.24 A hypothetic scheme of the time behaviour of the spike linked to the opening and closing of sodium and potassium channels. After longer time intervals a temporary hyperpolarization of the membrane is induced by reversed transport of potassium ions inside the nerve cell. Nernst potentials for Na+ and K+ are also indicated in the figure. 

Cardiac Action Potential In Vitro Purkinje Fibers. Intracellular recording of action potentials from cardiac Purkinje fibers isolated from dog or sheep ventricle. Measurement of maximum rate of depolarization and action potential duration to detect sodium and potassium channel interactions, respectively, according to recommendations in EM A CPMP Points to Consider document, CPMP 986/96 (1998). 

Roden, D.M. and George, A.L.J. (1997) Structure and function of cardiac sodium and potassium channels. The American Journal of Physiology, 273, H511-H525. 

Flecainide is a potent blocker of sodium and potassium channels with slow unblocking kinetics. (Note that although it does block certain potassium channels, it does not prolong the action potential or the QT interval.) It is currently used for patients with otherwise normal hearts who have supraventricular arrhythmias. It has no antimuscarinic effects. 

It should be noted that the myelin sheath helps to propagate the AP even faster down the neuron. The signal will "jump" from one node of Ranvier to the next (saltatory motion). The distribution of sodium and potassium channels is uneven in the myelinated regions, appropriate to the node and covered areas of the nerve. Should the myelin become stripped from a normally myelinated cell, then the electrical signal cannot... 

The 1960s saw the discovery of a number of specific channel-blocking agents. Tetrodotoxin, for example, from the fugu puffer fish, specifically blocks voltagegated sodium channels. This provided very convincing confirmation that the sodium and potassium channels of nerve axons really are separate from each other. It also allowed potassium channels in nerves to be studied on their own, permitted estimates of channel densities in the membrane to be made, and ultimately proved crucial in the biochemical isolation of sodium channels. 

Pyrethrins affect nerve membranes by modifying the sodium and potassium channels, resulting in depolarization of the membranes. Formulations of these insecticides frequently contain the insecticide synergist piperonyl butoxide [5- 2-(2-butoxyethoxy) ethoxymethyl -6-propyl-l,3-benzodioxole], which acts to increase the efficacy of the insecticide by inhibiting the cytochrome P450 enzymes responsible for the breakdown of the insecticide. 

Figure 16.2 Saltatory conduction. Myelin acts as an insulator to prevent current loss as the action potential travels down the axon. Sodium and potassium channels are clustered at the Nodes of Ranvier, where there is no myelin. Action potentials jump from one node to the next, reducing the overall membrane area involved in conduction, and speeding up electrical transmission.

Sodium and Potassium Channel Modulators Their Role in Neuroprotection Tihomir P. Obrenovich... 

Neurotoxins of scorpions especially represent ion channel toxins that mainly affect sodium and potassium channels. Several compounds represent neurotoxins that are directed selectively against insects.97 Na+ channel-specific a-, (3-, and 7-toxins are composed of 58-76 amino acids and contain four stabilizing disulfide bridges.98 The well-studied K+ channel-specific toxins (divided into at least nine distinct peptide subfamilies) bind to the extracellular face of the channel and comprise 29-39 amino acids stabilized by 3-4 disulfide bridges.99 Various Ca2+ channel scorpion toxins, antimicrobial peptides, and short insectotoxins active on Cl channels have been found.96... 

The variables m, n, and h are phenomenological variables that describe the observed gating of the sodium and potassium channels in response to changes in... 

Figure 7.8 Simulated action potential from the Flodgkin-Huxley model. The upper panel plots action potential for three different values of applied current. The lower panel plots the predicted conductances of the sodium and potassium channels for the case of Iapp = 6.2 qA-cm-2, for which sustained period firing of the nerve cell is predicted.

Cocaine and its metabolite block sodium and potassium channels and its use is also associated with QT interval prolongation. 

The pharmacological activity of decahydroquinoline ci5-195A and analogs in neuromuscular preparations appears to involve noncompetitive blockade both of nicotinic receptor-channels and of voltage-dependent sodium and potassium channels (see reviews in Refs. 3 and 5). Recently, both cis- and rra/i5-decahydroquinolines were shown to block ion flux through nicotinic receptor channels in pheochromocytoma cells and to enhance the rate of desensitization of such nicotinic channels (64,82). 

Chapter 5. Drugs that act on sodium and potassium channels... 

Scorpion venom is composed of many different fractions that can vary among the different scorpion species. These venom fractions act at different tissue receptor sites. Local tissue reaction is a result of the inflammatory response to the injected foreign proteins and enzymes making up the venom. The venom of Centruroides species contains several different neurotoxins. These toxins block the transmission of nerve impulses in the central nervous system and in muscles by blocking the transport of ions through sodium and potassium channels at the cellular level. Other venom components may decrease the heart rate by causing the release of acetylcholine. 

Tacrine has numerous mechanisms of action. The putative principle mechanism of action of tacrine for Alzheimer s disease is reversible inhibition of acetylcholinesterase (AChE), which thereby slows the breakdown of the chemical messenger acetylcholine (ACh) in the brain. In addition, tacrine blocks the sodium and potassium channels. 

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