Potassium channel blocking drugs

It is an alkaloid obtained from the bark of cinchona and is a dextro isomer of anti-malarial drug quinine. Its sodium channel blocking property results in an increased threshold for excitability and decreased automaticity. As a consequence of its potassium channel blocking properties, it prolongs action potential in most cardiac cells. 

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. 

Colatsky TJ, Follmer CH, Starmer CF (1990) Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias. Circulation 82 2235-2242... 

Type I antiarrhythmics appear to share a single receptor site in the sodium channel. It should be noted, however, that a number of type I drugs have other electrophysiologic properties. For instance, quinidine has potent potassium channel blocking activity (manifest predominantly at low concentrations), as does A-acetylprocainamide (manifest predominantly at high concentrations), the primary metabolite of procainamide. Additionally, propafenone has /3-blocking actions. 

Type III drugs specifically prolong refractoriness in atrial and ventricular fibers and include very different drugs that share the common effect of delaying repolarization by blocking potassium channels. 

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]. 

Lacerda, A.E., Kramer, J., Shen, K.Z., Thomas, D. and Brown, A.M. (2001) Comparison of block among cloned cardiac potassium channels by non-antiarrhythmic drugs. European Heart Journal Supplements, 3, K23-K30. 

Several classes of drugs, notably the antipsychotics, discussed in Chapter 34, interfere with dopaminergic transmission. In general, dopamine appears to be an inhibitory neurotransmitter. Five dopamine receptors have been identified the most important and best studied are the Dj. and D2.receptor groups. The Dj receptor, which increases cyclic adenosine monophosphate (cAMP) by activation of adenylyl cyclase, is located primarily in the region of the putamen, nucleus accum-bens, and in the olfactory tubercle. The D2 receptor decreases cAMP, blocks certain calcium channels, and opens certain potassium channels. 

Schematic diagram of the ion permeability changes and transport processes that occur during an action potential and the diastolic period following it. Yellow indicates inward (depolarizing) membrane currents blue indicates outward (repolarizing) membrane currents. Multiple subtypes of potassium and calcium currents, with different sensitivities to blocking drugs, have been identified. The right side of the figure lists the genes and proteins responsible for each type of channel or transporter.

Several first-generation Hi antagonists are potent local anesthetics. They block sodium channels in excitable membranes in the same fashion as procaine and lidocaine. Diphenhydramine and promethazine are actually more potent than procaine as local anesthetics. They are occasionally used to produce local anesthesia in patients allergic to conventional local anesthetic drugs. A small number of these agents also block potassium channels this action is discussed below (see Toxicity). 

TFP (5) was found to be a very effective blocker of human Kv2.1 potassium channels expressed in human glioblastoma cells [253]. As for other types of channels, for Kv2.1 the TFP-induced block was also dose-dependent (IC50 = 1.21 xM). Some of the other, non-phenothiazine drugs were even more effective blockers for the most potent, fluspirilene (an antipsychotic agent), substantial block was observed at 30 nM. 

The occurrence of cardiac toxicity was closely correlated with terfenadine use, and subsequent in vitro studies confirmed that terfenadine (but not fexofenadine) efficiently blocks cardiac potassium channels (14). A study in healthy volunteers treated concomitantly with terfenadine and ketoconazole found a linear relationship between trough terfenadine concentrations and QTC intervals. The QTC interval lengthened up to 110 millisecond at the highest plasma concentrations of 45 ng/mL (9). Thus, the direct inhibitory effect of terfenadine on cardiac potassium channels results in prolongation of cardiac repolarization, which is a well-known cause of ventricular arrhythmias. In one death in which terfenadine was implicated, plasma level of the drug was 55 ng/mL several hours after the last ingestion of the drug (when it normally should be undetectable). 

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