Disopyramide Verapamil

Although AGP is the most quantitatively important protein in the plasma binding of many basic drugs, it usually exhibits only low enantio-selectivity. This may have measurable pharmacokinetic and pharmacodynamic consequences, as is the case with, for instance, disopyramide, verapamil, and the p-blockers. More generally, however, clinically important effects due to enantioselective binding of drugs to AGP are much less frequently observed than for HSA. 

All antiarrhythmic dra are used cautiously in patients with renal or hepatic disease. When renal or hepatic dysfunction is present, a dosage reduction may be necessary. All patients should be observed for renal and hepatic dysfunction. Quinidine and procainamide are used cautiously in patients with CHF. Disopyramide is used cautiously in patients with CHF, myasthenia gravis, or glaucoma, and in men with prostate enlargement. Bretylium is used cautiously in patients with digitalis toxicity because the initial release of norepinephrine with digitalis toxicity may exacerbate arrhythmias and symptoms of toxicity. Verapamil is used cautiously in patients with a history of serious ventricular arrhythmias or CHF. Electrolyte disturbances such as hypokalemia, hyperkalemia, or hypomagnesemia may alter the effects of the antiarrhythmic dru . Electrolytes are monitored frequently and imbalances corrected as soon as possible... 

When two antiarrhythmic dragp are administered concurrently the patient may experience additive effects and is at increased risk for drug toxicity. When quinidine and procainamide are administered with digitalis, tiie risk of digitalis toxicity is increased. Hiarmacologic effects of procainamide may be increased when procainamide is administered with quinidine When quinidine is administered with the barbiturates or cimetidine, quinidine serum levels may be increased. When quinidine is administered with verapamil, there is an increased risk of hypotensive effects. When quinidine is administered with disopyramide, there is an increased risk of increased disopyramide blood levels and/or decreased serum quinidine levels. 

Antiarrhythmics (e.g., disopyramide, flecainide, and others) P-Blockers (e.g., propranolol, metoprolol, atenolol, and others) Calcium channel blockers (e.g., verapamil and others)... 

Class I compounds have both good solubility and permeability and generally offer no problems with regard to having a good absorption profile (e.g., acetaminophen, disopyramide, ketoprofen, metoprolol, nonsteroidal anti-inflammatory agents, valproic acid, verapamil). In general, one would not expect the presence of food to influence the absorption of this class... 

Drugs that may affect disopyramide include antiarrhythmics, beta blockers, cisapride, clarithromycin, erythromycin, fluoroquinolones, hydantoins, quinidine, thioridazine, rifampin, verapamil, and ziprasidone. Drugs that may be affected by disopyramide include quinidine, anticoagulants, and digoxin. 

Drugs that may affect flecainide include amiodarone, cimetidine, cisapride, disopyramide, propranolol, ritonavir, urinary acidifiers/alkalinizers, and verapamil. Smoking may also have an effect. Drugs that may be affected by flecainide include cisapride, propranolol, and digoxin. 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

Blockers, diltiazem, verapamil, disopyramide, NSAIDs, rosiglitazone... 

Figure 6.17 The classification of 42 drugs in the (solubility-dose ratio, apparent permeability) plane of the QBCS. The intersection of the dashed lines drawn at the cutoff points form the region of the borderline drugs. Key 1 acetyl salicylic acid 2 atenolol 3 caffeine 4 carbamazepine 5 chlorpheniramine 6 chlorothiazide 7 cimetidine 8 clonidine 9 corticosterone 10 desipramine 11 dexamethasone 12 diazepam 13 digoxin 14 diltiazem 15 disopyramide 16 furosemide 17 gancidovir 18 glycine 19 grizeofulvin 20 hydrochlorothiazide 21 hydrocortisone 22 ibuprofen 23 indomethacine 24 ketoprofen 25 mannitol 26 metoprolol 27 naproxen 28 panadiplon 29 phenytoin 30 piroxicam 31 propanolol 32 quinidine 33 ranitidine 34 salicylic acid 35 saquinavir 36 scopolamine 37 sulfasalazine 38 sulpiride 39 testosterone 40 theophylline 41 verapamil HC1 42 zidovudine.

DISOPYRAMIDE CALCIUM CHANNEL BLOCKERS Risk of myocardial depression and asystole when disopyramide is co administered with verapamil, particularly in the presence of heart failure Disopyramide is a myocardial depressant like verapamil and can cause ventricular tachycardia, ventricular fibrillation or torsades de pointes Avoid co administering verapamil with disopyramide if possible. If single-agent therapy is ineffective, monitor PR, BP and ECG closely watch for heart failure... 

Further clinical examples of potential stereoselective renal secretion of organic cations have been recently reported. A major metabolite of verapamil (D-617) is actively secreted by the kidney (59). Upon coadministration of dmetidine, the renal clearance of the S-D-617 isomer was significantly decreased, whereas the clearance of the R-D-617 metabolite was unaffected by dmetidine administration (59). Stereoselective renal secretion was suggested as the mechanism of this effect. However, it is not known if this metabolite is actually secreted by the organic cation transport system. The renal clearance of unbound S(+) disopyramide was... 

Figure 3 Drugs that display enantioselective binding to a,-acid glycoprotein. I, disopyramide II, propranolol III, verapamil and lY propafenone.

For enantiomeric drugs with low organ clearance, differences in renal or hepatic clearance between stereoisomers may reflect their free fraction in the plasma and not real stereoselectivity of the ability of the organ to remove the free enantiomers (intrinsic clearance) from the plasma. Clearance differences between stereoisomers of verapamil and disopyramide may be a function of plasma protein binding differences. In addition, volumes of distribution as well as concentration ratios of stereoisomers in body fluids to total plasma and blood are influenced by plasma protein binding. For example, the larger volume of distribution and greater total body clearance of R-disopyramide compared to the S isomer may be explained by the lower... 

Parameter Isomer Warfarin Ibuprofen Disopyramide PropranoF Verapamil ... 

Zipes DP, Troup PJ. New antiarrhythmic agents amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide, verapamil. Am J Cardiol 1978 41(6) 1005-24. 

Clinically important, potentially hazardous interactions with amiodarone, bepridil, diltiazem, disopyramide, floctafenine, quinidine, verapamil... 

Clinically important, potentially hazardous interactions with alfentanil, aminophylline, amisulpride, amoxicillin, ampicillin, anticonvulsants, astemizole, atorvastatin, benzodiazepines, bromocriptine, buprenorphine, bupropion, carbamazepine, cilostazol, ciprofloxacin, cisapride, clindamycin, colchicine, cyclosporine, dasatinib, digoxin, dihydroergotamine, diltiazem, disopyramide, enoxacin, eplerenone, ergotamine, eszopiclone, everolimus, fluconazole, fluoxetine, fluvastatin, gatifloxacin, HMG-CoA reductase inhibitors, imatinib, itraconazole, ketoconazole, lomefloxacin, lorazepam, lovastatin, methadone, methylprednisolone, methysergide, midazolam, mizolastine, moxifloxacin, nitrazepam, norfloxacin, ofloxacin, paroxetine, pimozide, pravastatin, quinolones, ranolazine, repaglinide, rupatadine, sertraline, sildenafil, simvastatin, sparfloxacin, sulpiride, tacrolimus, terfenadine, triazolam, troleandomycin, vardenafil, verapamil, vinblastine, warfarin, zaleplon, zolpidem, zuclopenthixol... 

Clinically important, potentially hazardous interactions with alcohol, amiodarone, beta-blockers, cimetidine, donidine, digoxin, diltiazem, disopyramide, ephedrine, epinephrine, ergot alkaloids, guanethidine, halothane, isoprenaline, lidocaine, noradrenaline, NSAIDs, phenylephrine, quinidine, reserpine, verapamil... 

Tamargo et al gave a very recent review.139 They point out that KATP channels are inhibited by ATP and activated by Mg ADP, so that the channel activity is influenced by the ATP/ADP ratio. They also draw attention to the fact that mitochondrial KATp channel is responsible for ischemic preconditioning. They suggest that these channels are not blocked only by sulfonylureas, but also by many antiarrhythmic drugs, such as bretylium, disopyramide, flecainide and propafenone, and also by diltiazem and verapamil, but not by amiodarone or dronedarone, which will be addressed later. 

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