Sodium blockade

The carbamazepine molecule shares structural homology with that of the tricyclic antidepressants, and has weak antidepressant activity. The depression of cortical excitability, due to sodium blockade, also makes it useful as adjunct therapy in the treatment of acute mania. 

Quinidine blocks sodium channels and also blocks potassium channels. Thus, phase 0 of the cardiac action potential is blunted, due to the sodium blockade, and the plateau phase (2) is... 

The Class I antiarrhythmic agents inactivate the fast sodium channel, thereby slowing the movement of Na" across the cell membrane (1,2). This is reflected as a decrease in the rate of development of phase 0 (upstroke) depolarization of the action potential (1,2). The Class I agents have potent local anesthetic effects. These compounds have been further subdivided into Classes lA, IB, and IC based on recovery time from blockade of sodium channels (11). Class IB agents have the shortest recovery times (t1 ) Class lA compounds have moderate recovery times (t 2 usually <9 s) and Class IC have the longest recovery times (t 2 usually >9 s). 

Elestolol sulfate is a nonselective, ultrashort acting P-adrenoceptor blocker. It has no ISA and produces weak inhibition of the fast sodium channel. The dmg is under clinical investigation for supraventricular tachyarrhythmias, unstable angina, and acute MI. In humans, flestolol has hemodynamics and electrophysiologic effects similar to those of other P-adrenoceptor blockers. The pharmacokinetics of flestolol are similar to those of esmolol. It is 50 times more potent than esmolol and the elimination half-life is 7.2 min. Recovery from P-adrenoceptor blockade is 30—45 min after stopping iv infusions. The dmg is hydrolyzed by tissue esterases and no active metabohtes of flestolol have been identified (41). 

An imidazole derivative which is also a hypotensive agent by virtue of adrenergic a-2-receptor blockade is imiloxan (75). Its synthe.sis begins by conversion of 2-cyanomethyl-1,4-benzodioxane (72) to its iminosMhylether with anhydrous HC in clhanol (73). Reaction of the latter with aminoacetaldehyde diethylacetal and subsequent acid treatment produces the imidazole ring (74). Alkylation of 74 with ethyl iodide mediated by sodium hydride completes the synthesis [251. 

The amide local anaesthetic lidocaine may also be used as an antianhythmic for ventricular tachycardia and exra-systoles after injection into the blood circulation. Drugs with high lipid solubility such as bupivacaine cannot be used for these purposes because their prolonged binding to the channel may induce dysrhythmias or asystolic heart failure [3]. Systemically applied lidocaine has also been used successfully in some cases of neuropathic pain syndromes [4]. Here, electrical activity in the peripheral nervous system is reduced by used-dependent but incomplete sodium channel blockade. 

Moorman, J.R. Yee, R Bjomsson, T. Starmer, CF. Grant, A.O. and Strauss, H.C. pKa does not predict pH potentiation of sodium ehannel blockade by lidocaine and W6211 in guinea pig ventricular myocardium. 

Tokuyama H, Ueha S, Kurachi M, et al. The simultaneous blockade of chemokine receptors CCR2, CCR5 and CXCR3 by a non-peptide chemokine receptor antagonist protects mice from dextran sodium sulfate-mediated colitis. Int Immunol 2005 17 1023-1034. 

The mechanism of action of these anesthetics involves the blockade of sodium channels in the membrane of the second-order sensory neuron. The binding site for these anesthetics is on a subunit of the sodium channel located near the internal surface of the cell membrane. Therefore, the agent must enter the neuron in order to block the sodium channel effectively. Without the influx of sodium, neurons cannot depolarize and generate an action potential, so the second-order sensory neuron cannot be stimulated by impulses elicited by pain receptors associated with the first-order sensory neuron. In other words, the pain signal is effectively interrupted at the level of the spinal cord and does not travel any higher in the CNS. In this way, the brain does not perceive pain. 

Figure 1.1 The dopamine transporter terminates the action of released dopamine by transport back into the presynaptic neuron. Dopamine transport occurs with the binding of one molecule of dopamine, one chloride ion, and two sodium ions to the transporter the transporter then translocates from the outside of the neuronal membrane into the inside of the neuron.22 Cocaine appears to bind to the sodium ion binding site. This changes the conformation of the chloride ion binding site thus dopamine transport does not occur. This blockade of dopamine transport potentiates dopaminergic neurotransmission and may be the basis for the rewarding effects of cocaine.

The typical form of proarrhythmia caused by the type Ic antiarrhythmic drugs is a rapid, sustained, monomorphic VT with a characteristic sinusoidal QRS pattern that is often resistant to resuscitation with cardioversion or overdrive pacing. Some clinicians have had success with IV lidocaine (competes for the sodium channel receptor) or sodium bicarbonate (reverses the excessive sodium channel blockade). 

There have been several studies that underscore the importance of unbound concentration in cell-based studies of receptor function. In a model study of the effect of plasma protein binding on the renal transport of organic anions using the expression of various organic anion transporters (OATPs) in Xenopus oocytes, the transport of ochratoxin A, methotrexate, and estrone sulfate was found to be strongly inhibited by the addition of human serum albumin to the culture medium [16]. Similarly, the addition of oq-acid glycoprotein was found to reverse the blockade of sodium-ion current by cocaine in a preparation of cardiac myocytes [17]. 

At the cellular level, the major electrophysiological effect appears to be rate-dependent blockade of sodium channels [22]. The onset for this Class I effect (64 + 9% of the final depression of between the first and second beat of the train) was similar to that for Class IB agents [23]. The offset rate (recovery of from rate-dependent depression) for amiodarone was 1.48 s. This value falls between those seen for Class IB agents (200-500 ms) and lA agents (2.3-12.2 s) [23]. Amiodarone inhibited the binding of pH]ba-trochotoxinin A 20a-benzoate to the sodium channel, suggesting that it binds to inactivated sodium channels [24]. 

Solvents, specifically surrounding the sodium cation, lower its effect. In the presence of a crown ether, including and blockading the sodium cation, the rate of the final product formation is entirely restored. 

Several other agents are under study that are designed to produce combined blockade of COX and lipoxygenase. One such example is tenidap sodium, a novel antiarthritic agent, which also appears to block IL-1 formation and action [140]. 

Antiarrhythmics Vaughn Williams Classification Class I Sodium Channel Blockade... 

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. 

Four main mechanisms of action underlie the beneficial pharmaceutical effect of AED (1) blockade of the voltage-dependent sodium channels (2) increased GABAergic inhibition of neurotransmission (3) blockade of glutaminergic transmission (4) blockade of type T calcium channels. AEDs are thus classed according to their known predominant effect ... 

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