Verapamil interaction with other drugs

Drug interactions are multiple but of special interest is the interaction with other AADs such as quinidine and verapamil, both increasing the serum concentration. 

After identifying Pgp as a major cause of MDR in in vitro cell studies and discovering that verapamil (a blocker) modulates Pgp activity, researchers have devoted a tremendous effort to discovering other Pgp modulators (inhibitors) that have high binding affinity to Pgp without other biological activities and also have minimal pharmacokinetic interactions with anticancer drugs [213]. 

Calcium-channel blockers in current clinical usage affect the slow L-type channel. They are usually classified by their chemical structure, which determines their selectivity for vascular smooth muscle over myocardium, and hence their potential to slow the heart rate (negative inotropic activity) see Table 23. T, (below). Interactions due to additive inotropic effects will therefore apply only to the benzothiazepine (diltiazem) and phenyla-Ikylamine-type (verapamil) calcium-channel blockers, and usually not to the dihydropyridine-type (e.g. nifedipine) calcium-channel blockers. All three types of calcium-channel blocker will have additive hypotensive effects with other drugs with blood-pressure lowering activity. 

Mibefradil is a verapamil-like agent with a potentially attractive haemodynamic profile. It is a vasodilator, which also causes a reduction in heart rate, whereas it is devoid of negative inotropic activity. Some of its properties are attributed to its influence of calcium channels of the T- and N-types. Unfortunately, the compound has been withdrawn because of multiple interactions with various other drugs. 

As noted earlier, lithium is contraindicated in patients with unstable congestive heart failure or the sick sinus node syndrome ( 307, 328). In older patients or those with prior cardiac histories, a pretreatment ECG should be obtained. Except for the potential adverse interactions with diuretics, the concomitant use of other cardiac drugs is generally safe. Because verapamil may lower serum levels of lithium, however, more careful monitoring may be required to assure continued therapeutic effects (329). Some data also indicate that verapamil may predispose to lithium neurotoxicity. Conversely, increased lithium levels leading to toxicity has occurred with methyidopa and enalapril. When antihypertensive therapy is necessary, b-blockers are a reasonable choice when lithium is coadministered. 

Verapamil, diltiazem Nonselective block of L-type calcium channels in vessels and heart Reduced vascular resistance, cardiac rate, and cardiac force results in decreased oxygen demand Prophylaxis of angina, hypertension, others Oral, IV, duration 4-8 h Toxicity Atrioventricular block, acute heart failure constipation, edema Interactions Additive with other cardiac depressants and hypotensive drugs... 

Bebawy et al. [186] demonstrated that CPZ (9) and vinblastine inhibited each other s transport in a human lymphoblastic leukemia cell line (CCRF-CEM/VLBioo). CPZ (9) reversed resistance to vinblastine but not to fluores-cently labeled colchicine and it increased resistance to colchicine. Colchicine was supposed to be transported from the inner leaflet of the membrane and vinblastine from the outer leaflet. CPZ (9) was assumed to be located in the inner membrane leaflet where it interacts with anionic groups of phospholipids and it may inhibit vinblastine transport via allosteric interactions. The authors concluded that transport of P-gp substrates and its modulation by CPZ (9) (or verapamil (79)) are dependent on substrate localization inside the membrane. Contrary to CPZ (9) location in the inner leaflet of the membrane, other modulators and substrates of P-gp were proved to be rather localized within the interface region of the membrane. The location of seven P-gp substrates and two modulators within neutral phospholipid bilayers was examined by NMR spectroscopy by Siarheyeva et al. [129]. The substrates and the modulators of P-gp were found in the highest concentrations within the membrane interface region. The role of drug-lipid membrane interactions in MDR and its reversal was reviewed in detail elsewhere [53,187]. 

Drugs metabolized by CYP that interact with cimetidine include, but are not limited to, the following lidocaine, quinidine, midazolam, triazolam, nifedipine, verapamil, and fentanyl (4). In each instance, inhibition of CYP by cimetidine results in reduced metabolic clearance and increases in serum concentrations of the other drug, which can lead to the expected toxicity and adverse experiences characteristic of the other drug. 

Inhibitors of OATP transport are typically ster-ically bulky compounds, including anions, cations, and neutral compounds (95). Various medications have been shown to interact with OATPs, including HMG CoA reductase inhibitors, cyclosporine, quinidine, rifampin, ketoconazole, verapamil, and certain protease inhibitors. Cyclosporine and rifampin have relatively high ratios of plasma concentration to Ki, suggesting the potential for clinically significant drug-drug interactions via modulation of OATP. On the other hand, plasma concentrations of pravastatin are... 

The choice of Pgp inhibitor is not without importance. When measuring fluorescence one always has to be aware of direct interactions with fluorescence of the dye not related to the Pgp function. This can be checked in Pgp-nega-tive cell lines and AML samples. In addition, effects on other transporters than Pgp may theoretically occur, which are unwanted if one intends to have a Pgp-specific method. On the other hand, if one wishes to determine the effect of a certain drug on the cellular accumulation of a probe, whether or not related to one specific transporter, this is not an unwanted side-effect. For instance, Pgp modulators such as verapamil or cyclosporin A may be less Pgp-specific in combination with certain dyes. (For an extensive discussion of this matter see ref. 4.)... 

Cardiac glycosides interact with many other drugs some increase the risk of toxicity (for example amiodarone and verapamil) and others reduce it (for example cholestyramine, colestipol and antacids), but also reduce therapeutic effect. 

Established interactions but of uncertain clinical importance. The manufacturers of nifedipine advise caution when it is used with diltiazem because of possible increases in nifedipine levels. They say a reduction in the dose of nifedipine should be considered. Verapamil is predicted to interact similarly. Information about the use of combinations of other ealei-um-channel blockers appears to be lacking. However, the UK manufacturers of nimodipine advise that if it is used with other antihypertensive drugs, including other calcium-channel bloekers sueh as nifedipine, diltiazem, or verapamil, blood pressure monitoring and eareful dose titration of nimodipine should be carried out with possible reduetion or discontinuation of the other calcium-channel bloeker. 

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