Phenytoin Disopyramide

Procainamide, quinidine, quinine, disopyramide, phenytoin, and (i-adrenergic blockers, calcium channel blockers... 

Ideally, unbound (versus total) drug concentrations should be monitored, especially for drugs that have a narrow therapeutic range, are highly protein bound (free fraction less than 20%), and have marked variability in the free fraction (e.g., phenytoin, disopyramide). 

Drugs that may be affected by itraconazole include alfentanil, almotriptan, alprazolam, amphotericin B, aripiprazole, benzodiazepines, buspirone, busulfan, calcium blockers, carbamazepine, cilostazol, cisapride, corticosteroids, cyclosporine, digoxin, disopyramide, docetaxel, dofetilide, eletriptan, epierenone, ergot alkaloids, haloperidol, HMG-CoA reductase inhibitors, hydantoins (phenytoin), hypoglycemic agents, oral midazolam, phosphodiesterase type 5 inhibitors, pimozide, polyenes, protease inhibitors, quinidine, rifamycins, sirolimus, tacrolimus, tolterodine, triazolam, trimetrexate, vinca alkaloids, warfarin, and zolpidem. 

In the presence of phenytoin, the metabolism of disopyramide is increased (reducing its effective concentration) and the accumulation of its metabolites is also increased, thereby increasing the probability of anticholinergic adverse effects. Rifampin also stimulates the hepatic metaboUsm of disopyramide, reducing its plasma concentration. 

Phenytoin lacks the anticholinergic properties of quinidine, disopyramide, and procainamide. However, the direct actions of phenytoin on the A-V node facilitate transmission. 

Albumin concentration Drugs such as phenytoin, salicylates, and disopyramide are extensively bound to plasma albumin. Albumin levels are low in many disease states, resulting in lower total drug concentrations. 

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.

Mechanism of action. Na -channel blocking antiarrhythmics resemble most local anesthetics in being cationic amphiphilic molecules (p.206 exception phenytoin, p.191). Possible molecular mechanisms of their inhibitory effects are outlined on p.202 in more detail. Their low structural specificity is reflected by a low selectivity toward different cation channels. Besides the Na channel. Carotid 1C channels are also likely to be blocked. Accordingly, cationic amphiphilic antiarrhythmics affect both the depolarization and repolarization phases. Depending on the substance, AP duration can be increased (Class IA), decreased (Class IB), or remain the same (Class IC). Antiarrhythmics representative of these categories include Class IA—quinidine, procainamide, ajmaline, disopyramide Class IB—lidocaine, mexile-tine, tocainide Class IC—flecainide, propafenone. 

DISOPYRAMIDE ANTIEPILEPTICS- BARBITURATES, PHENYTOIN Disopyramide levels are 1 by phenobarbital and primidone Phenobarbital and primidone induce the hepatic metabolism of disopyramide Watch for poor response to disopyramide check serum levels if necessaiy... 

ANTIARRHYTHMIC agents (Class I agents, e.g. disopyramide, flecainide. lignocaine. procainamide, quinidine) are sodium-channel blockers and are mainly used to treat atrial and ventricular tachycardias (see antiarrhythmic agents). ANTIEPILEPTICS have a number of mechanisms of action, but some appear to have a component involving modulation of sodium-channel function, e.g. carbamaxepine and phenytoin (see anticonvulsants). 

Clinically important, potentially hazardous interactions with amiodarone, astemizole, bepridil, carbamazepine, chloroquine, cisapride, clarithromycin, dihydroergotamine, disopyramide, ergotamine, grapefruit juice, halofantrine, haloperidol, itraconazole, ketoconazole, methadone, moxifloxacin, phenobarbital, phenytoin, pimozide, procainamide, quinidine, rifampicin, ritonavir, sotalol, St John s wort, telithromycin, terfenadine, voriconazole... 

Na+ Anticonvulsant drugs Class I antiarrhythmics Diuretic drugs Local anesthetic drugs Carbamazepine, phenytoin, valproic acid lA Disopyramide, procainamide, quinidine IB Lidocaine, mexiletine, phenytoin, tocainide IC Encainide, flecainide, propafenone Amiloride Bupivacaine, cocaine, lidocaine, mepivacaine, tetracaine... 

Figure 13.35. Disopyramide (40), mianserin (41), and (5)-para-hydroxyphen3doin (S-42), the chiral metabolite of phenytoin (25)shown in Fig. 13.22.

CYP2C8 <5 1-2 Disopyramide Amiodarone Clozapine Diclofenac Fluvastatin Nicardipine Paclitaxel Retinoic acid Rosiglitazone Torsemide Repaglinide Amiodarone Celecoxib Felodipine Nicardipine Fluoxetine Ketoconazole Ritonavir Indinavir Troglitazone Zafirlukast Retinoic acid Clotrimazole Phenobarbital Dexamethasone Gemfibrozil Rifampin Phenytoin Ritonavir... 

Moricizine (600 to 900 mg/day given every 8 hours in three equally divided doses) is indicated in the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that are life threatening. Because of the proarrhythmic effects of moricizine, its use should be reserved for patients in whom the benefits of treatment outweigh the risks. Moricizine is a class 1C antiarrhythmic agent with potent local anesthetic activity and myocardial-membrane-stabilizing effects. It shares some of the characteristics of the class lA (disopyramide, procainamide, or quinidine), of class IB (lidocaine, mexiletene, phenytoin, or tocainide), or class 1C agents (encainide, flecainide, or propafenone) in that it reduces the fast inward current carried by sodium ions. Moricizine shortens phase 2 and 3... 

Also analyzed acebutolol, acepromazine, acetaminophen, acetazolamide, acetophenazine, albuterol, amitriptyline, amobarbital, amoxapine, antipsrrine, atenolol, atropine, azata-dine, baclofen, benzocaine, bromocriptine, brompheniramine, brotizolam, bupivacaine, buspirone, butabarbital, butalbital, caffeine, carbamazepine, cetirizine, chlorqyclizine, chlordiazepoxide, chlormezanone, chloroquine, chlorpheniramine, chlorpromazine, chlorpropamide, chlorprothixene, chlorthalidone, chlorzoxazone, cimetidine, cisapride, clomipramine, clonazepam, clonidine, clozapine, cocaine, codeine, colchicine, qyclizine, (yclo-benzaprine, dantrolene, desipramine, diazepam, diclofenac, diflunisal, diltiazem, diphenhydramine, diphenidol, dipheno late, dipyridamole, disopyramide, dobutamine, doxapram, doxepin, droperidol, encainide, ethidium bromide, ethopropazine, fenoprofen, fentanyl, flavoxate, fluoxetine, fluphenazine, flurazepam, flurbiprofen, fluvoxamine, fii-rosemide, glutethimide, glyburide, guaifenesin, haloperidol, homatropine, hydralazine, hydrochlorothiazide, hydrocodone, hydromorphone, hydro g chloroquine, hydroxyzine, ibuprofen, imipramine, indomethacin, ketoconazole, ketoprofen, ketorolac, labetalol, le-vorphanol, lidocaine, loratadine, lorazepam, lovastatin, loxapine, mazindol, mefenamic acid, meperidine, mephenytoin, mepivacaine, mesoridazine, metaproterenol, methadone, methdilazine, methocarbamol, methotrexate, methotrimeprazine, methoxamine, methyl-dopa, methylphenidate, metoclopramide, metolazone, metoprolol, metronidazole, midazolam, moclobemide, morphine, nadolol, nalbuphine, naloxone, naphazoline, naproxen, nifedipine, nizatidine, norepinephrine, nortriptyline, oxazepam, oxycodone, oxymetazo-line, paroxetine, pemoline, pentazocine, pentobarbital, pentoxifylline, perphenazine, pheniramine, phenobarbital, phenol, phenolphthalein, phentolamine, phenylbutazone, phenyltoloxamine, phenytoin, pimozide, pindolol, piroxicam, pramoxine, prazepam, prazosin, probenecid, procainamide, procaine, prochlorperazine, procyclidine, promazine, promethazine, propafenone, propantheline, propiomazine, propofol, propranolol, protriptyline, quazepam, quinidine, quinine, racemethorphan, ranitidine, remoxipride, risperidone, salicylic acid, scopolamine, secobarbital, sertraline, sotalol, spironolactone, sulfinpyrazone, sulindac, temazepam, terbutaline, terfenadine, tetracaine, theophylline, thiethyl-perazine, thiopental, thioridazine, thiothixene, timolol, tocainide, tolbutamide, tolmetin, trazodone, triamterene, triazolam, trifluoperazine, triflupromazine, trimeprazine, trimethoprim, trimipramine, verapamil, warfarin, xylometazoline, yohimbine, zopiclone... 

Extracted metabolites, ethosxiximide, primidone, phenobarbital, phenytoin Simultaneous acetaminophen, N-acetylprocainamide, aspirin, ampicillin, caffeine, ce-phapirin, chloramphenicol, digoxin, disopyramide, hexobarbital, indomethacin, lidocaine, mephobarbital, methsuximide, nafcillin, pentobarbital, phenylethylmalonamide, procainamide, quinidine, salicylic acid, secobarbital, sulfamerazine, sulfamethazine, terbutaline, tetracycline, theobromine, theophylline... 

Noninterfering acetaminophen, N-acetylprocainamide, amikacin, amitriptyline, ampicil-lin, carbamazepine, cefamandole, cefazolin, cefoperazone, cefotaxime, cefoxitin, ceftazidime, ceftizoxime, cephalexin, cephalothin, cephapirin, chloramphenicol, ciprofloxacin, clonazepam, (yclosporine, desipramine, digoxin, disopyramide, ethosuximide, gentamicin, haloperidol, imipramine, kanamycin, lidocaine, mezlocillin, netilmicin, nortriptyline, phenobarbital, phenytoin, primidone, procainamide, propranolol, quinidine, salicylic acid, streptomycin, sulfamethoxazole, theophylline, thiamphenicol, ticarcillin, tobramycin, trimethoprim, vancomycin... 

---