Sodium channel effects, concentrations

In cell culture preparations, diphenylhydantoin, carbamazepine and valproate have been shown to reduce membrane excitability at therapeutically relevant concentrations. This membrane-stabilizing effect is probably due to a block in the sodium channels. High concentrations of diazepam also have similar effects, and the membrane-stabilizing action correlates with the action of these anticonvulsants in inhibiting maximal electroshock seizures. Intracellular studies have shown that, in synaptosomes, most anticonvulsants inhibit calcium-dependent calmodulin protein kinase, an effect which would contribute to a reduction in neurotransmitter release. This action of anticonvulsants would appear to correlate with the potency of the drugs in inhibiting electroshock seizures. The result of all these disparate actions of anticonvulsants would be to diminish synaptic efficacy and thereby reduce seizure spread from an epileptic focus. 

In the presence of TTX, the response of the preparation to GABA was not altered even after perfusion with deltamethrin for sixty minutes. Figure 5 shows dose response curves to GABA obtained before and after perfusion of 10 mM deltamethrin. This concentration of deltamethrin is 1,000 times greater than the threshold concentration for an effect on the sodium channels, indicating that the sodium channel effect is much more important to the poisoning process than any effect on the GABA system. 

Besides sodium channels, other ion channels such calcium- and potassium channels as well as certain ligand-gated channels are affected by local anaesthetics. However, this plays only a minor role for nerve block but may have more impact on adverse effects induced by systemical concentrations of these drags. 

Tamplin et. al. (54) observed that V. cholerae and A. hydrophila cell extracts contained substances with TTX-like biological activity in tissue culture assay, counteracting the lethal effect of veratridine on ouabain-treated mouse neuroblastoma cells. Concentrations of TTX-like activity ranged from 5 to 100 ng/L of culture when compared to standard TTX. The same bacterial extracts also displaced radiolabelled STX from rat brain membrane sodium channel receptors and inhibited the compound action potential of frog sciatic nerve. However, the same extracts did not show TTX-like blocking events of sodium current when applied to rat sarcolemmal sodium channels in planar lipid bilayers. 

Introduced initially for absence seizures, this drug is now known to be effective in and used to treat tonic lonic seizures and most types of epilepsy. It was found to inhibit GABA transaminase and so elevate GABA concentrations and inhibition. This is achieved, however, over a slower time-course than its anti-seizure effect, especially experimentally, which is now thought to be due to its phenytoin-like, use-dependent block of sodium channels. Since, unlike phenytoin, the full effect of valproate takes some weeks to develop, its slower effect on GABA metabolism and activity should not be ignored. 

In contrast to the metabotropic effects described for presynaptic kainate receptors in CA1 (90,94), the effects of kainate in CA3 appear to be mediated by direct depolarization of the presynaptic terminals. The kainate-induced facilitation is not sensitive to antagonists of other receptors (e.g., GABAb), and can be mimicked by elevating the extracellular potassium concentration (77,100). It has been proposed that the facilitation is owing to increased calcium influx that is induced by modest depolarization of the terminals by kainate receptors, whereas a strong depolarization, in response to activation of a larger receptor population, causes the sodium channels to inactivate and thereby depresses transmission (77,84,88,100-102). 

The anticonvulsant properties of the drug would appear to be due to its ability to inhibit fast sodium channels, which may be unrelated to its psychotropic effects. Like lithium, it has been shown to decrease the release of noradrenaline and reduce noradrenaline-induced adenylate cyclase activity unlike lithium, it seems to have little effect on tryptophan or 5-HT levels in patients at therapeutically relevant concentrations. It also reduces dopamine turnover in manic patients and increases acetylcholine... 

Dofetilide s mechanism of action involves blockade of the cardiac ion channel that carries the rapid component of the delayed rectifier potassium current, IKr. Dofetilide inhibits IKr with no significant effects on other repolarizing potassium currents (e.g., IKs, IKl) over a wide range of concentrations. At plasma concentrations within the therapeutic range, dofetilide has no effect on sodium channels or on either i- or p-adreno-ceptors. 

Lithium has numerous pharmacologic effects. It is able to cross through sodium channels, competing with monovalent and divalent cations in cell membranes (AHFS, 2000). Animal studies have shown that lithium at a serum level of 0.66 + — 0.08 mEq/L can increase the amphetamine-induced release of serotonin (5-hydroxytryptamine [5-HT]) and the concentrations of a serotonin metabolite (e.g., 5-hydroxyindoleacetic acid [5-HIAA]) in the perifornical hypothalamus (PFH) of rats before and after chronic lithium chloride administration (Baptista et ah, 1990), a mechanism possibly involved in lithium s antidepressant effect. The precise neurobiological mechanisms through which lithium reduces acute mania and protects against recurrence of illness remain uncertain (Lenox and Hahn,... 

The duration of action of a local anaesthetic is proportional to the time that the drug remains bound to the sodium channels. Measures that prolong contact time will prolong the duration of the local anaesthetic effect. Cocaine has a vasoconstricting effect on blood vessels and prevents its own absorption. Many local anaesthetics are prepared with adrenaline (epinephrine) in order to achieve this effect. Concentrations are usually of the order of 1 200000 or more dilute than this. Care should be exercised when using adrenaline-containing solutions in the presence of halothane as it is known to sensitise the myocardium to the effects of catecholamines. 

Local anesthetic action, also known as "membrane-stabilizing" action, is a prominent effect of several 3 blockers (Table 10-2). This action is the result of typical local anesthetic blockade of sodium channels (see Chapter 26) and can be demonstrated experimentally in isolated neurons, heart muscle, and skeletal muscle membrane. However, it is unlikely that this effect is important after systemic administration of these drugs, since the concentration in plasma usually achieved by these routes is too low for the anesthetic effects to be evident. These membrane-stabilizing 3 blockers are not used topically on the eye, where local anesthesia of the cornea would be highly undesirable. Sotalol is a nonselective 3-receptor antagonist that lacks local anesthetic action but has marked class III antiarrhythmic effects, reflecting potassium channel blockade (see Chapter 14). 

Important differences between the available calcium channel blockers arise from the details of their interactions with cardiac ion channels and, as noted above, differences in their relative smooth muscle versus cardiac effects. Sodium channel block is modest with verapamil, and still less marked with diltiazem. It is negligible with nifedipine and other dihydropyridines. Verapamil and diltiazem interact kinetically with the calcium channel receptor in a different manner than the dihydropyridines they block tachycardias in calcium-dependent cells, eg, the atrioventricular node, more selectively than do the dihydropyridines. (See Chapter 14 for additional details.) On the other hand, the dihydropyridines appear to block smooth muscle calcium channels at concentrations below those required for significant cardiac effects they are therefore less depressant on the heart than verapamil or diltiazem. 

Quinidine has actions similar to those of procainamide it slows the upstroke of the action potential and conduction, and prolongs the QRS duration of the ECG, by blockade of sodium channels. The drug also prolongs the action potential duration by blockade of several potassium channels. Its toxic cardiac effects include excessive QT interval prolongation and induction of torsade de pointes arrhythmia. Toxic concentrations of quinidine also produce excessive sodium channel blockade with slowed conduction throughout the heart. 

The mechanism of action of carbamazepine appears to be similar to that of phenytoin. Like phenytoin, carbamazepine shows activity against maximal electroshock seizures. Carbamazepine, like phenytoin, blocks sodium channels at therapeutic concentrations and inhibits high-frequency repetitive firing in neurons in culture (Figure 24-4). It also acts presynaptically to decrease synaptic transmission. These effects probably account for the anticonvulsant action of carbamazepine. Binding studies show that carbamazepine interacts with adenosine receptors, but the functional significance of this observation is not known. 

The cardiovascular effects of local anesthetics result in part from direct effects of these drugs on the cardiac and smooth muscle membranes and from indirect effects on the autonomic nervous system. As described in Chapter 14, local anesthetics block cardiac sodium channels and thus depress abnormal cardiac pacemaker activity, excitability, and conduction. At extremely high concentrations, local anesthetics can also block calcium channels. With the notable exception of cocaine, local anesthetics also depress myocardial contractility and produce direct arteriolar dilation, leading to systemic hypotension. Cardiovascular collapse is rare, but has been reported after large doses of bupivacaine and ropivacaine have been inadvertently administered into the intravascular space. 

In small doses, local anesthetics can depress posttetanic potentiation via a prejunctional neural effect. In large doses, local anesthetics can block neuromuscular transmission. With higher doses, local anesthetics block acetylcholine-induced muscle contractions as a result of blockade of the nicotinic receptor ion channels. Experimentally, similar effects can be demonstrated with sodium channel-blocking antiarrhythmic drugs such as quinidine. However, at the doses used for cardiac arrhythmias, this interaction is of little or no clinical significance. Higher concentrations of bupivacaine (0.75%) have been associated with cardiac arrhythmias independent of the muscle relaxant used. 

Cocaine inhibits the presynaptic reuptake of the neurotransmitters norepinehrine, serotonin, and dopamine at synaptic junctions. This results in increased concentrations in the synaptic cleft. Since norepinephrine acts within the sympathetic nervous system, increased sympathetic stimulation is produced. Physiological effects of this stimulation include tachycardia, vasoconstriction, mydriasis, and hyperthermia.3 CNS stimulation results in increased alertness, diminished appetite, and increased energy. The euphoria or psychological stimulation produced by cocaine is thought to be related to the inhibition of serotonin and dopamine reuptake. Cocaine also acts as a local anesthetic due to its ability to block sodium channels in neuronal cells.3... 

Hydantoins Ethotoin (Peganone) Fosphenytoin (Cerebyx) Mephenytoin (Mesantoin) Phenytoin (Dilantin) Primary effect is to stabilize membrane by blocking sodium channels in repetitive-firing neurons higher concentrations may also influence concentrations of other neurotransmitters (GABA, norepinephrine, others)... 

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