Effects on calcium channels

The pharmacological profile of amiodarone is extremely complex. On acute exposure the compound slows conduction (indicative of Class I elec-trophysiological activity) [17], exhibits both a- and y9-adrenergic antagonism [18], and may have an effect on calcium channels [19]. The Class III elec-trophysiological activity is generally not manifest on acute exposure but may take several days to weeks to reach maximal effect in patients [20,21]. 

These novel tetrameric bromotyrosine metabolites display a range of biological activities, including effects on calcium channels (1900), lipoxygenase inhibition (1772), tumor angiogenesis inhibition (1901), and endothelial cell anti-proliferation (1902). Syntheses of several bastadins have been accomplished (1903,1904). 

Relationship between membrane binding sites for calcium channel blocking drugs and effects on calcium channels in intact cells 275... 

CHANNEL BLOCKING DRUGS AND EFFECTS ON CALCIUM CHANNELS IN... 

Low-Friedrich, I. Schoeppe, W. (1991). Effects of calcium channel blockers on stress protein synthesis in cardiac myocytes. J. Cardiovasc. Pharmacol. 17,800-806. 

Obviously, the effects of tamoxifen and derivatives and of raloxifene on L-type calcium channels from aortic and other blood vessels would reduce vascular smooth muscle contractility. This action, in synergy with the aforementioned effect on BK channels, would reduce blood peripheral resistance and blood pressure, which may partially account for the reduction in cardiovascular risk (Da Costa et al. 2004 Trump et al. 1992) (Fig. 4.1). 

Neurotransmitter release induced by potassium-dependent depolarization is a physiologically relevant way to investigate pyrethroid effects on calcium-dependent neurotransmitter release since this process is independent of voltage-sensitive sodium channels [71]. Furthermore, potassium-stimulated calcium influx and subsequent neurotransmitter release by synaptosomes is blocked by a variety of voltage-sensitive calcium channel antagonists but not by TTX [4, 71, 72]. 

Landon EJ, Naukam RJ, Sastry BVR. 1986. Effects of calcium channel blocking agents on calcium and centrilobular necrosis in the liver of rats treated with hepatotoxic agents. Biochem Pharmacol 35 697-705. 

However, the reverse is not necessarily true all compounds that block the hERG channels do not prolong action potentials. Part of the reason lies in the fact that many compounds have a mixed effect on ion channels, particularly due to the blocking effect on both hERG and the L-type calcium channel [21], which is responsible for phase 2 of the cardiac action potential (Figure 16.1). Examples for such dual-blockers include bepridil, verapamil and mibefradil [22], all blocking hERG and L-type calcium channels at the therapeutic concentrations. However, only verapamil has nearly no cardiac liabilities. 

Barrios, M. and Bayens, J.M. Differential effects of calcium channel blockers and stimulants on morphine withdrawal in vitro, Eur. J. Pharmacol. 1988, 152, 175-178. 

Gurdal, H., Sara, Y., Tulunay, F.C. Effects of Calcium Channel Blockers on formalin-induced nociception and inflammation in rats, Pharmacology 1992, 44, 290-296. 

Mason RP. Effects of calcium channel blockers on cellular apoptosis implications for carcinogenic potential. Cancer. 1999 85 2093-2102. 

Fig. 3.20 Comparison of the perturbation effect of calcium channel blocker drugs on parameter S of 16-PC in liposomal membranes at 25 and 37 °C. Co, control NIF, nifedipine ...

Tab. 3.15 The effects of calcium channel-blocking drugs on the main phase transition ofdimyristoylphosphatidylcholine (DMPC) adapted from ref. 155.

The Class IV drugs are calcium channel blockers. They decrease the inward current carried by calcium, resulting in a decrease in the rate of Phase 4 spontaneous depolarization and slowed conduction in tissues dependent on calcium currents, such as the AV node (Figure 17.12). Although voltage-sensitive calcium channels occur in many different tissues, the major effect of calcium-channel blockers is on vascular smooth muscle and the heart. 

Further studies have revealed that pumiliotoxin B interacts with voltage-dependent sodium channels to elicit an increased influx of sodium ions (101,102) and, in brain and heart preparations, a stimulation of phosphoino-sitide breakdown (101,103-106). The phosphoinositide breakdown can, via inositol trisphosphate, cause release of calcium from internal storage sites. The cardiotonic activity of pumiliotoxin B and various congeners and synthetic analogs correlates well with the stimulation of phosphoinositide breakdown (104,105). A number of studies on stimulation of sodium uptake by pumiliotoxin B and inhibition by local anesthetics and other agents have appeared (106-108). The effects of pumiliotoxin B on neuromuscular preparations have been reinterpreted as due primarily to effects on sodium channels, although additional direct effects on calcium mobilization remain possible (109). It has recently been proposed that pumiliotoxin B enhances the rate of activation of sodium channels (110). One characteristic effect of pumiliotoxin B is to elicit repetitive firing in neurons, apparently because of effects on sodium channel function (109-111). 

CALCIUM CHANNEL BLOCKERS ANAESTHETICS - LOCAL Case reports of severe 1 BP when bupivacaine epidural was administered to patients on calcium channel blockers Additive hypotensive effect both bupivacaine and calcium channel blockers are cardiodepressant in addition, epidural anaesthesia causes sympathetic block in the lower limbs, which leads to vasodilatation and 1 BP Monitor BP closely. Preload intravenous fluids prior to the epidural... 

CALCIUM CHANNEL BLOCKERS MAOIs t antihypertensive effect of calcium channel blockers when co-administered with MAOIs Additive hypotensive effects postural 1 BP is a side-effect of MAOIs Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)... 

CALCIUM CHANNEL BLOCKERS NON-DEPOLARIZING t effect of non-depolarising muscle relaxants with parenteral calcium channel blockers the effect is less certain with oral therapy. In two cohort studies, vecuronium requirements were halved in patients on diltiazem. Nimodipine does not seem to share this interaction Uncertain postulated that ACh release at the synapse is calcium dependent 1 calcium concentrations at the nerve ending may 1 ACh release, which in turn prolongs the nerve blockade Monitor nerve blockade carefully in patients on calcium channel blockers, particularly near to the end of surgery, when muscle relaxation may be prolonged and difficult to reverse... 

CALCIUM CHANNEL BLOCKERS X-RAY CONTRAST SOLUTIONS t hypotensive effect when intravenous ionic contrast solutions are given to patients on calcium channel blockers Additive hypotensive effect Consider using a non-ionic X-ray contrast solution for patients on calcium channel blockers... 

Calcium-dependent processes relevant to pharmacological intervention mainly include pace-making in the heart, and contraction in heart and smooth muscle. These are affected by dmgs that either act on calcium channels directly, or on other receptors that will have some downstream effect on the cytosolic availability of calcium. Exemples are the p-and ttj-adrenergic receptors (see below). 

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