Na+-channel inhibitors

Salty tastants act directly on Na+ channels in the PM of cells on the tongue surface. Direct passage of Na+ through these channels causes depolarization and thence signalling to the CNS. Much (but not all) salt taste perception is inhibited by the voltage-sensitive Na+ channel inhibitor amiloride (see Chapter 4) and evidently some salt perception also occurs via amiloride-insensitive channels. 

Prototypic inhibitor of the family of Na/H exchangers and of epithelial Na+ channels. 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Renin-Angiotensin-Aldosterone System Epithelial Na+ Channels ACE Inhibitors... 

The first inhibitor of NHE, amiloride, was identified in 1982. This drug is a potassium-sparing diuretic that also inhibits the sodium-calcium exchanger and the conductive Na+ channel. Not all the NHE isoforms are inhibited equally by amiloride NHE1 and 2 are responsive, NHE5 is partially responsive and NHE3, 4 and 7 are resistant. Other weak and non-specific inhibitors are clonidine and cimetidine. 

Two classes of inhibitors for influenza virus are currently available (Hayden 2006). The M2 proton channel inhibitors amantadine and rimantadine and the neuraminidase (NA) inhibitors oseltamivir carboxylate and zanamivir. Chapter 5 provides more details about the class of NA inhibitors. 

Parasympathomimetics and sym-pathomimetics act at membrane receptors for visceromotor neurotransmitters. The plasmalemma also harbors the sites of action of cardiac glycosides (the Na/K-ATPases, p. 130), of Ca + antagonists (Ca2+ channels, p. 122), and of agents that block Na channels (local anesthetics p. 134, p. 204). An intracellular site is the target for phosphodiesterase inhibitors (e.g., amrinone, p. 132). 

SUN-8075 is also a propanolol derivative, but it does not act as a S-blocker it is a dual Na+/Ca + channel blocker and channel inhibitor. It is being studied in Phase I clinical trials as a therapeutic agent for acute stroke. 

Flecainide is a selective inhibitor of Na" " channels and does not act on channels. It is... 

Inhibitors of Na+channels in the collecting ducts Mineralocorticoid-receptor antagonists Side effects of diuretics INTRODUCTION... 

These agents inhibit the Na-i- ion channei in the iuminai epitheiium. This causes hyperpolarisation of the iuminai membrane and iimits the transfer of cations across the iuminai surface. Flyperpolarisation not only prevents the reabsorption of Na-i- but aiso reduces the excretion of intracellular cations such as K+, Ca2+, Fi+ and Mg2+. The abiiity of sodium ion channel inhibitors to reduce the excretion of K+ is used to conserve body K+ in patients who are taking thiazide or loop diuretics and for this reason they are more commoniy known as the K-i-sparing diuretics. They are rarely used alone because their diuretic action is weak, instead they are administered in combination with thiazide or ioop diuretics for their antikaiuretic effect. Combination therapy is also synergistic when used in the treatment of hypertension. 

Many fish species, over 700 species worldwide, are either directly toxic or upon ingestion are poisonous to humans. A classic example is the toxin produced by the puffer fishes (Sphaeroides spp.) called tetrodotoxin (TTX). Tetrodotoxin is concentrated in the gonads, liver, intestine, and skin, and poisonings occurs most frequently in Japan and other Asian countries where the flesh, considered a delicacy, is eaten as fugu. Death occurs within 5 to 30 minutes and the fatality rate is about 60%. TTX is an inhibitor of the voltage-sensitive Na channel (like saxitoxin) it may also be found in some salamanders and may be bacterial in origin. 

Figure 1 presents the structure of amiloride and that of amiloride analogues that are known to be the most potent inhibitors of epithelium Na+ channels and the Na+/H+ exchanger. Other derivatives of guanidinium that are unrelated to amiloride and that have antihypertensive properties also block the Na+/H+ exchanger (Frelin etal., 1986). 

Fig. 1.9 Two modes of cydization of the side chain in -blockers yield the noradrenaline (NA) reuptake inhibitor viloxazine (mode 1) and the potassium channel blocker cromakalim (mode 2).

---