Potassium channels blockade

III Potassium channel blockade Slows atrioventricular conduction Amiodarone, sotolol... 

In this example, clarithromycin, a potent CYP3A inhibitor blocks the principal pathway of pimozide metabolism (CYP3A), and plasma concentrations of pimozide increase. A higher pimozide concentration (a pharmacokinetic effect) is associated with prolongation of QT c in EKG readings and potentially fatal torsades de pointes (via potassium channel blockade, a pharmacodynamic effect see Flockhart et al., 2000, May-hew et ah, 2000). As exemplified by this vignette, the... 

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). 

Altemus KL, Levine MS (1996) Potassium channel blockade does not alter the modulatory effects of dopamine in neostriatal slices. Brain Res 718 212-216. 

There has been one report of hypokalemia (2.2 mmol/1), probably due to potassium channel blockade, after administration of high-dose intravenous lidocaine (8 mg/1) for raised intracranial pressure (SEDA-21, 136). 

Muller T, Moller T, Berger T, Schnitzer J, Kettenmann H (1992b) Calcium channel entry through kainate receptors and resulting potassium channel blockade in Bergmann glial cells. Science 256 1563-1566. 

Bepridil prolongs phase 2 of the cardiac action potential, due to the inhibition of calcium flux. The potential may also decrease in amplitude (phase 0) with the inhibition of fast sodium channels. A decrease in the slope of phase 3, due to the potassium channel blockade and decreased slope of phase 4, may also be evident. The net effect is a prolongation of the action potential and an increase in ERP. 

Vorperian VR, Zhou Z, Mohammad S, Hoon TJ, Studenik C, January CT. Torsade de pointes with an antihistamine metabolite potassium channel blockade with desmethylastemizole. JAm Coll Cardiol (1996) 28, 1556-61. 

FJ. Ortega, J. Gimeno-Bayon, J.E Espinosa-Parrilla, J.L. Carrasco, M. Batlle, M. Pugliese, N. Mahy, and M.J. Rodriguez, ATP-dependent potassium channel blockade strengthens microglial neuroprotection after hypoxia-ischemia in rats. Exp. Neurol. 235(1), 282-296 (2012). 

Melgari D, Zhang Y, El Harchi A, Dempsey CE, Hancox JC (2015) Molecular basis of hERG potassium channel blockade by the class Ic antiarrhythmic flecainide. J Mol Cell Cardiol 86 42-53... 

An alternative approach to stimulate cholinergic function is to enhance the release of acetylcholine (ACh). Compounds such as the aminopyridines increase the release of neurotransmitters (148). The mechanism by which these compounds modulate the release of acetylcholine is likely the blockade of potassium channels. However, these agents increase both basal (release in the absence of a stimulus) and stimulus-evoked release (148). 4-Aminopyridine [504-24-5] was evaluated in a pilot study for its effects in AD and found to be mildly effective (149). 

The behavioral effects of phencyclidines may be due to their blockade of potassium channels. Proc Natl Acad Sci USA 78 7792-7795, 1981. 

H receptor activation induces depolarizing responses in many brain areas, notably hypothalamus, thalamus and cerebral cortex. In vertebrate brain, many of these effects are mediated by opening cation channels. H,-induced excitation can also occur by blockade of KUak conductances [ 1 ]. In other cases, however, H, receptors can attenuate neuronal excitation by activating certain voltagegated potassium channels. Most of the H, receptor-induced conductance changes are mediated by the IP3-Ca2+ cascade. 

Several studies support the notion that the basic mechanism by which many drugs prolong the QT interval is related to blockade of potassium currents. For instance, several antihistamines, antibacterial macrolides, fluoroquinolones and antipsychotics were shown to inhibit the rapid component of the delayed rectifier K+ current (fKr) in electrophysiological studies and to block potassium channels encoded by hERG [37-42]. 

Milnes, J.T., Dempsey, C.E., Ridley, J.M., Crociani, O., Arcangeli, A., Hancox, J.C. and Witchel, H.J. (2003) Preferenhal closed channel blockade of hERG potassium currents by chemically synthesised BeKm-1 scorpion toxin. FEBS Letters, 547, 20-26. 

By blocking sodium channels, procainamide slows the upstroke of the action potential, slows conduction, and prolongs the QRS duration of the ECG. The drug also prolongs the action potential duration by nonspecific blockade of potassium channels. The drug may be somewhat less effective than quinidine (see below) in suppressing abnormal ectopic pacemaker activity but more effective in blocking sodium channels in depolarized cells. 

Dofetilide has class 3 action potential prolonging action. This action is effected by a dose-dependent blockade of the rapid component of the delayed rectifier potassium current, IKr, and the blockade of IKr increases in hypokalemia. Dofetilide produces no relevant blockade of the other potassium channels or the sodium channel. Because of the slow rate of recovery from blockade, the extent of blockade shows little dependence on stimulation frequency. However, dofetilide does show less action potential prolongation at rapid rates because of the increased importance of other potassium channels such as IKs at higher frequencies. 

A 23-year-old woman took chlorpropamide 5-10 g. She needed assisted respiration and cardiac pacing for bradycardia (probably due to blockade of potassium channels), fluid infusion, and forced diuresis for 3 days. Notwithstanding continuous glucose infusion and glucose boluses she relapsed into severe hypoglycemia with convulsions. Only on day 27 was her urine free of chlorpropamide and her blood glucose normal. 

---