Medical brain Notes 3

  Drugs that act on sodium and potassium channels After discussing the basic principles of ion channel func-tion in membrane excitation, it is important to note that for each major ion species there is a multitude of channels with specialized roles in different cell types and cell compart-ments. This is particularly striking in the case of K +  and Ca ++  channels. It was noted before that K +  channels may be either constitutively open or controlled by electrical fields or ligand binding. These major functional classes are struc-turally different from each other; this is apparent already by comparing the number of transmembrane helices con-tained in each of the channel proteins (Figure 5.1). While K V  channels mediate the repolarization following an action potential, the basal K +  permeability at the resting potential – the one that actually keeps the resting potential close to the K +  equilibrium potential – is largely due to constitutive-ly open ...

  Local anesthetics Sodium channels are responsible for the propagation of action potentials in nerve fibers. Local anesthetics are blockers of sodium channels. They will thus intercept the propagation of action potentials along nerve fibers and in this way, among other things, prevent perception of pain. We have seen before that drug receptors may be (in fact, typically are) allosteric molecules. This also applies to voltage-gated channels. With these, the force or energy required for transition from the resting to the active state is normally provided not by ligand binding but by an elec-trical field. We have seen as well that drugs may interact differentially with the inactive state and the active state of a receptor. With voltage-gated channels, we actually have three different conformational states – they may be closed, open or inactivated. The functional effects of local anes-thetics are related to their interactions with both the open and the inactivated states (Figure 5.3)....

  Sodium channel blockers as antiarrhythmic agents A second major clinical application for lidocaine and related sodium channel blockers consists in the suppression of arrhythmias in the heart, which most commonly arise there as a consequence of some hypoxic tissue damage. To un-derstand this usage, we will briefly look at some details of heart physiology.   As noted before, the heart has its own conduction system for creating rhythmic excitations and propagating them in an orderly fashion to the muscle cells. The primary pace-maker is the sinoatrial node, which sits somewhere in the wall of the right atrium (Figure 5.8a). We have already seen before that it utilizes calcium and potassium but not sodium channels to create a spontaneous rhythm (Figure 5.8b, top). Specialized muscle fibers conduct each action potential first to the atrio-ventricular node and from there to the bundle of His, the Purkinje's fibers and finally the muscle cells. The lower parts of the conduction sys...

  Sodium channel blockers in epilepsia Another field of application for sodium channel blockers is epilepsia. While epileptic seizures are a diverse and com-plex phenomenon, a key feature consists in bursts of excess excitatory activity of neurons in the brain. Sodium chan-nel blockers will reduce nerve cell excitability, and they are thus one of the mainstays of anti-epileptic treatment. As but one example out of many 7 , Figure 5.10 shows pheny-toin (or diphenylhydantoine).   Properties of phenytoin are   • good penetration of blood brain barrier; • action on several cation channels besides Na V. The contribution of these to the therapeutic effect is unsettled;   • strong enzyme induction (hepatic metabolism, CYP3A3). This gives rise to multiple drug interactions.   These characteristics are quite common among antiepilep-tic drugs.

  Potassium channel blockers Among the potassium channels, it is not the voltage-gated ones but a ligand-gated channel that constitutes the main drug target. This is the ATP-sensitive `inward rectifier' (K ir ) channel 8 . The ATP sensitivity is conferred by a second membrane protein with which it is associated, the so-called sulfonylurea receptor (Figure 5.11a). The sulfonylurea re-ceptor is homologous to the family of `ABC' ( A TP- b inding  c assette) transporters that occurs in both prokaryotes and   eukaryotes. These proteins mediate the ATP-driven mem-brane transport of a wide variety of substances, including the extrusion of toxic compounds 9 . The sulfonylurea recep-tor, however, serves a different purpose: The conforma-tional change induced by binding of ATP is relayed to the K +  channel, which thus becomes responsive to ATP: High levels of ATP inhibit the channel, while lower levels cause it to open. This is schematically depicted in Figure 5.11b. The sulf...

  Potassium channel openers Another practically important class of drugs that also in-teract with the sulfonylurea receptor are potassium channel openers. In keeping with our expectations, they will reduce membrane excitability. These are mostly targeted at the K ir  channels in the vascular smooth muscle cells (Figure 5.13).   A reduction of smooth muscle tension in the vessel walls will reduce the blood pressure, and high blood pressure ac-cordingly is the usual rationale for their use. Their binding sites on the receptor molecule may be the same as those of the sulfonylurea derivatives, or not; correspondingly, they may or may not resemble the latter drugs in structure (Fig-ure 5.14). The similarity is apparent with diazoxide. This drug actually also affects the pancreatic  β -cells, and accord-ingly brings about reduced insulin secretion and elevated blood glucose, rendering it unsuitable for long-term use. The second drug shown (minoxidil) does not have this sid...