Pharmacy Blog – Dr Vibore

A man with ventricular arrhythmias successfully treated with propafenone had a marked fall in his plasma propafenone level from 993 to 176 nanograms/mL within 12 days of starting to take rifampicin 450mg twice daily. Levels of two active metabolites of propafenone, 5-hydroxypropafenone and N-depropylpropafenone, changed from 195 to 64 nanograms/mL and from 110 to 192 nanograms/mL, respectively. His arrhythmias returned, but 2 weeks after stopping rifampicin his arrhythmias had disappeared and propafenone and its 5-hydroxy andN-depropyl metabolites had returned to acceptable levels (1411, 78 and 158 nanograms/mL respectively) (See reference number 1). In a study in young healthy subjects, rifampicin 600mg daily for 9 days reduced bioavailability of a single 300mg oral dose of propafenone from 30 to 10 % in CYP2D6 extensive metabolisers, and from 81 to 48 % in those with low levels of CYP2D6 (poor metabolisers). Consider Genetic factors,, for more information on metaboliser status. QRS prolongation decreased during enzyme induction. In contrast, in this study, rifampicin had no substantial effect on pharmacokinetics of propafenone given intravenously (See reference number 2). Similar findings were reported in a further study by same research group in healthy elderly subjects (See reference number 3).

Rifampicin induces CYP3A4/1A2-mediated metabolism and phase II glucuronidation of propafenone

An established and clinically relevant metabolic drug interaction. The dosage of oral propafenone will need increasing during concurrent use of rifampicin (See reference number 3). Alternatively, if possible, authors of case report(See reference number 1) advise use of another antibacterial, where possible, because of probable difficulty in adjusting propafenone dosage.

Castel JM,Cappiello E, Leopaldi D, Latini R. Rifampicin lowers plasma concentrations ofpropafenone and its antiarrhythmic effect. Br J Clin Pharmacol (1990) 30, 155–6.

Dilger K,Greiner B, Fromm MF, Hofmann U, Kroemer HK, Eichelbaum M. Consequences ofrifampicin treatment on propafenone disposition in extensive and poor metabolizers of CYP2D6. Pharmacogenetics (1999) 9, 551–9.

Dilger K,Hofmann U, Klotz U. Enzyme induction in the elderly: Effect of rifampin on thepharmacokinetics and pharmacodynamics of propafenone. Clin Pharmacol Ther (2000) 67, 512–20.

When procainamide and amiodarone are used together QTinterval prolonging effects are increased, therefore combination should generally be avoided. Serum procainamide levels areincreased by about 60 % and N-acetylprocainamide levels byabout 30 % by amiodarone. If combination is used, dosageof procainamide will need to be reduced to avoid toxicity.

Twelve patients were stabilised on procainamide (2 to 6 g daily,or about 900mg every 6 hours). When amiodarone (600 mg loading dose every 12 hrs for 5 to 7 days,then 600mg daily) was also given their mean serum procainamide levels rose by 57 % (from 6.8 to 10.6 micrograms/mL) and their serum levels of metabolite N-acetylprocainamide (NAPA) rose by 32 % (from 6.9 to 9.1 micrograms/mL). Procainamide levels increased by more than 3 micrograms/mL in 6 patients. The increases usually occurred within 24 hours,but in other patients they occurred as late as 4 or 5 days. Toxicity was seen in 2 patients. Despite lowering procainamide dosages by 20%, serum procainamide levels were still higher (at

7 micrograms/mL) than before amiodarone was started (See reference number 1)

In another study,intravenous procainamide was given once before (at a mean dose of 13 mg/kg), and once during (at a 30 % reduced dose: mean

9.2 mg/kg) use of amiodarone 1.6 g daily for 7 to 14 days. Amiodarone decreased clearance of procainamide by 23 % and increased its elimination half-life by 38%. Both drugs prolonged QRS and QTc intervals, and extent of prolongation was significantly greater with combination than either drug alone (See reference number 2).

The mechanism behind pharmacokinetic interaction is not understood. The QT prolonging effects of two drugs would be expected to be additive

Information appears to be limited to these studies, but interaction would seem to be established and clinically important. The use of amiodarone with procainamide further prolongs QTc interval, which can increase risk of torsade de pointes. Therefore, combination should generally be avoided. The UK manufacturers of amiodarone contraindicate its use with class Ia antiarrhythmics such as procainamide,(See reference number 3) whereas US manufacturers of amiodarone recommend that such combined therapy should be reserved for life-threatening ventricular arrhythmias incompletely responsive to either drug alone and recommend that procainamide dosage should be reduced by one-third (See reference number 4). See also Drugs that prolong QT interval + Other drugs that prolong QT interval interaction. This is similar to recommendation made by authors of pharmacokinetic studies, who suggest that dosage of procainamide may need to be reduced by 20 to 50%. They also suggest that serum levels should be monitored and patients observed for adverse effects (See reference number 1,2). Remember that interaction can develop within 24 hours.

Saal AK,Werner JA, Greene HL, Sears GK, Graham EL. Effect of amiodarone on serum quinidine and procainamide levels. Am J Cardiol (1984) 53, 1264–7.

Windle J,Prystowsky EN, Miles WM, Heger JJ. Pharmacokinetic and electrophysiologic interactions of amiodarone and procainamide. Clin Pharmacol Ther (1987) 41, 603–10.

Cordarone X (Amiodarone hydrochloride). Sanofi-Aventis. UK Summary of product characteristics,April 2006.

Cordarone (Amiodarone hydrochloride). Wyeth Pharmaceuticals. US Prescribing information,May 2007.

The absorption of mexiletine is reduced following myocardial infarction,and very markedly reduced and delayed if diamorphineor morphine is used concurrently. A higher loading dose may beneeded if oral mexiletine is required during first few hoursfollowing a myocardial infarction.

A pharmacokinetic study showed that mean plasma levels of mexiletine (400 mg orally followed by 200mg 2 hrs later) in first 3 hrs were more than 50 % lower in 6 patients who had suffered a myocardial infarction and who had been given diamorphine 5 to 10mg or morphine 10 to 15mg than in 4 patients who had not been given opioids. In addition, AUC0-8 was 38.6 % lower in those who had received opioids (See reference number 1).

In a further study about prophylactic use of mexiletine, same authors found that plasma mexiletine levels 3 hrs after first oral dose were 31 % lower in 10 patients who had received opioids than in 6 patients who had not. These patients were from a subset who were subsequently shown not to have had a myocardial infarction (See reference number 1). In another similar trial of mexiletine in acute myocardial infarction,use of diamorphine was associated with low plasma mexiletine levels at 3 hours, and possible reduced efficacy of mexiletine. In this study, pretreatment with intravenous metoclopramide tended to reduce effect of diamorphine on mexiletine absorption,(See reference number 2) although this was not noted in other report (See reference number 1).

The reduced absorption of mexiletine would seem to result from inhibition of gastric emptying by opioids. Other mechanisms probably contribute to delayed clearance of mexiletine

An established interaction although information is limited. The delay and reduction in absorption would seem to limit value of oral mexiletine during first few hrs after a myocardial infarction, particularly if opioid analgesics are used. The manufacturer suggests that a higher load

ing dose of oral mexiletine may be preferable in this situation. Alternatively,an intravenous dose of mexiletine may be given. In addition, they note that it may be necessary to titrate dose against therapeutic effects and adverse effects (See reference number 3).

Pottage A,Campbell RWF, Achuff SC, Murray A, Julian DC, Prescott LF. The absorption oforal mexiletine in coronary care patients. Eur J Clin Pharmacol (1978) 13, 393–9.

Smyllie HC,Doar JW, Head CD, Leggett RJ. A trial of intravenous and oral mexiletine in acutemyocardial infarction. Eur J Clin Pharmacol (1984) 26, 537–42.

Mexitil (Mexiletine). Boehringer Ingelheim Ltd. UK Summary of product characteristics,May2003.

Amiodarone does not affect clearance of mexiletine

Clinical evidence,mechanism, importance and management

The clearance of mexiletine in 10 patients did not differ before and after 1,3 and 5 months concurrent use of amiodarone. In addition, clearance of mexiletine did not differ between these patients and 155 other patients not taking amiodarone (See reference number 1).

Class Ib antiarrhythmics are usually associated with shortening of QT interval, and could therefore be expected to reduce QT prolongation and risk of torsade de pointes seen with amiodarone alone (for examples of this effect of mexiletine see also Mexiletine + Beta blockers interaction,

and Mexiletine + Quinidine interaction. However, note that UK manufacturer of mexiletine(See reference number 4)says that it may exacerbate arrhythmias [as all antiarrhythmics may], but also that it may be used concurrently with amiodarone. The two drugs have been used together successfully (See reference number 5,6).

Yonezawa E,Matsumoto K, Ueno K, Tachibana M, Hashimoto H, Komamura K, Kamakura S, Miyatake K, Tanaka K. Lack of interaction between amiodarone and mexiletine in cardiacarrhythmia patients. J Clin Pharmacol (2002) 42, 342–6.

Tartini R,Kappenberger L, Steinbrunn W. Gefährliche Interaktionen zwischen Amiodaron undAntiarrhythmika der Klasse I. Schweiz Med Wochenschr (1982) 112, 1585–7.

Boehringer Ingelheim. Personal Communication,July 1995.

Mexitil (Mexiletine). Boehringer Ingelheim Ltd. UK Summary of product characteristics,May2003.

Waleffe A,Mary-Rabine L, Legrand V, Demoulin JC, Kulbertus HE. Combined mexiletineand amiodarone treatment of refractory recurrent ventricular tachycardia. Am Heart J (1980) 100, 788–93.

Hoffmann A,Follath F, Burckhardt D. Safe treatment of resistant ventricular arrhythmias witha combination of amiodarone and quinidine or mexiletine. Lancet (1983) i, 704–5.

The observation that 3 patients had unusually low plasma mexiletine levels while taking phenytoin prompted a pharmacokinetic study in 6 healthy subjects. After taking phenytoin 300mg daily for a week, mean AUC and half-life of a single 400mg dose of mexiletine were reduced by an average of about 50 % (half-life reduced from 17.2 to 8.4 hours) (See reference number 1).

The most likely explanation is that phenytoin increases metabolism of mexiletine by cytochrome P450 isoenzyme CYP1A2

Information seems to be limited to this report(See reference number 1) but interaction appears to be established. It seems likely that fall in mexiletine levels will be clinically important in some individuals. Monitor for mexiletine efficacy,and where possible levels. Raise dosage if necessary.

1. Begg EJ,Chinwah PM, Webb C, Day RO, Wade DN. Enhanced metabolism of mexiletine afterphenytoin administration. Br J Clin Pharmacol (1982) 14, 219–23.

Clinical evidence,mechanism, importance and management

A retrospective study,covering a 6-year period in 29 hospitals, identified 29 patients (27 available for review) who received lidocaine for prophylaxis or treatment of cocaine-associated myocardial infarction. No patient exhibited bradycardia,sustained ventricular tachycardia or ventricular fibrillation, and no patients died (See reference number 1).

Both lidocaine and cocaine exhibit class I antiarrhythmic effects and are proconvulsants. Lidocaine may potentiate cardiac and CNS adverse effects of cocaine. Therefore use of lidocaine for cocaine-associated myocardial infarction is controversial. The lack of adverse effects in this study may have been due to delays of more than 5 hrs between last exposure to cocaine and lidocaine therapy. These authors(See reference number 1) and others(See reference number 2,3) consider that cautious use of lidocaine does not appear to be contraindicated in patients with cocaine-associated myocardial infarction who require antiarrhythmic therapy. However,extra care should be taken in patients who receive lidocaine shortly after cocaine (See reference number 1).

Shih RD,Hollander JE, Burstein JL, Nelson LS, Hoffman RS, Quick AM. Clinical safety oflidocaine in patients with cocaine-associated myocardial infarction. Ann Emerg Med (1995) 26, 702–6.

Derlet RW. More on lidocaine use in cocaine toxicity. J Emerg Nurs (1998) 24,303.

Friedman MB. Is lidocaine contraindicated with cocaine? J Emerg Nurs (1997) 23,520.

Clinical evidence,mechanism, importance and management

A 71-year-old woman who had undergone kidney transplantation 7 years earlier and who was taking amlodipine,losartan, furosemide, chlortalidone, calcitriol, aspirin, prednisone, ciclosporin, cyclophosphamide and insulin was also treated with flecainide, which controlled her paroxysmal atrial fibrillation. Atorvastatin was then restarted for hypercholesterolaemia and benziodarone 100mg daily (because of intolerance to allopurinol) was added to treat hyperuricaemia. Three days later she presented with asthenia and poor overall condition and later an ECG showed QRS prolongation of 169 milliseconds (21% increase) caused by complete right bundle branch block with a previous anterior hemiblock,QTc interval prolongation of 482 milliseconds (22% increase) and PR interval prolongation of 203 milliseconds (18% increase). Creatinine levels were about 127 micromol/L,creatine phosphokinase 354 units/L and urea 155 mg/dL. Atorvastatin was stopped because of mild rhabdomyolysis. Flecainide and benziodarone were discontinued because an interaction was also suspected and symptoms resolved within 48 hours, with ECG then showing values close to baseline. Flecainide was restarted and dose gradually increased to 100mg daily (See reference number 1).

It was suggested that benziodarone may inhibit cytochrome P450 isoenzyme CYP2D6 which is concerned with metabolism of flecainide (See reference number 1). Note that benziodarone is chemically related to amiodarone,which has a similar effect, see Flecainide + Amiodarone interaction. Mild renal

insufficiency in patient may also have contributed to reduced flecainide elimination

1. Gormaz CL,Page JCG, Fuentes FL. Pharmacological interaction between flecainide and benziodarone. Rev Esp Cardiol (2003) 56, 631–2.

After taking phenobarbital 100mg daily for 21 days, half-life and AUC of a single 200mg dose of disopyramide were reduced by about 35%. The apparent metabolic clearance more than doubled, and fraction recovered in urine as metabolite increased. Sixteen healthy subjects took part in study and no significant differences were seen between those who smoked and those who did not (See reference number 1).

It seems probable that phenobarbital (a known enzyme inducer) increases metabolism of disopyramide by liver, and thereby increases its loss from body.

This interaction appears to be established,but its clinical importance is uncertain. The extent to which it would reduce control of arrhythmias by disopyramide is unknown, but monitor effects and serum levels of disopyramide if phenobarbital is added or withdrawn. The manufacturer of disopyramide(See reference number 2) recommends avoiding using it in combination with inducers of cytochrome P450 isoenzyme CYP3A, such as phenobarbital. Other barbiturates would be expected to interact similarly.

Kapil RP,Axelson JE, Mansfield IL, Edwards DJ, McErlane B, Mason MA, Lalka D, Kerr CR.Disopyramide pharmacokinetics and metabolism: effect of inducers. Br J Clin Pharmacol (1987) 24, 781–91.

Rythmodan Capsules (Disopyramide). Sanofi-Aventis. UK Summary of product characteristics,November 2005.

An isolated report describes cardiac failure in a patient given ajmaline with lidocaine. Quinidine causes a very considerableincrease in plasma levels of ajmaline, and phenobarbital appears to cause a marked reduction.

Clinical evidence,mechanism, importance and management

A study(See reference number 2) in 4 healthy subjects found that if a single 200mg oral dose of quinidine was given with a single 50mg oral dose of ajmaline, AUC of ajmaline was increased 10- to 30-fold and maximum plasma concentrations increased from 18 to 141 nanograms/mL. Another single-dose

study in 5 healthy subjects found that metabolism of ajmaline was inhibited by quinidine, possibly because quinidine becomes competitively bound to enzymes that metabolise ajmaline (See reference number 3).

Therefore clinical effects of ajmaline would be expected to be markedly diminished in those taking phenobar

Bleifeld W. Side effects of antiarrhythmics. Naunyn Schmiedebergs Arch Pharmacol (1971) 269,282–97.

Hori R,Okumura K, Inui K-I, Yasuhara M, Yamada K, Sakurai T, Kawai C. Quinidine-induced rise in ajmaline plasma concentration. J Pharm Pharmacol (1984) 36, 202–4.

Köppel C,Tenczer J, Arndt I. Metabolic disposition of ajmaline. Eur J Drug Metab Pharmacokinet (1989) 14, 309–16.

Köppel C,Wagemann A, Martens F. Pharmacokinetics and antiarrhythmic efficacy of intravenous ajmaline in ventricular arrhythmia of acute onset. Eur J Drug Metab Pharmacokinet (1989) 14, 161–7.

This section is mainly concerned with class I antiarrhythmics, which also possess some local anaesthetic properties, and with class III antiarrhythmics. Antiarrhythmics that fall into other classes are dealt with under beta blockers,, digitalis glycosides, , and calcium-channel blockers, . Some antiarrhythmics that do not fit into Vaughan Williams classification (see table 1 below,(below)) are also included in this section (e.g. adenosine). Interactions in which antiarrhythmic drug is affecting substance, rather than drug whose activity is altered, are dealt with elsewhere.

It is difficult to know exactly what is likely to happen if two antiarrhythmics are used together. The hope is always that a combination will work better than just one drug, and many drug trials have confirmed that hope, but sometimes combinations are unsafe. Predicting unsafe combinations is difficult, but there are some very broad general rules that can be applied if general pharmacology of drugs is understood.

If drugs with similar effects are used together, whether they act on myocardium itself or on conducting tissues, total effect is likely to be increased (additive). The classification of antiarrhythmics in table 1 below, (see below) helps to predict what is likely to happen, but remember that classification is not rigid so drugs in one class can share some characteristics with others. The following sections deal with some examples.

(a) Combinations of antiarrhythmics from same class

The drugs in class Ia can prolong QT interval so combining drugs from this class would be expected to show an increased effect on QT interval. This prolongation carries risk of causing torsade de pointes arrhythmias (see monograph, Drugs that prolong QT interval + Other drugs that prolong QT interval interaction). It would also be expected that negative inotropic effects of quinidine would be additive with procainamide or any of other drugs within class Ia. For safety therefore it is sometimes considered best to avoid drugs that fall into same subclass or only to use them together with caution.

Class III antiarrhythmics such as amiodarone can also prolong QT interval, so they would also be expected to interact with drugs in other classes that do same, namely class Ia drugs (see Drugs that prolong QT interval + Other drugs that prolong QT interval interaction). Verapamil comes into class IV and has negative inotropic effects, so it can interact with other drugs with similar effects, such as beta blockers, which fall into class III. For safety you should always look at whole drug profile and take care with any two drugs, from any class, that share a common pharmacological action.

Class I: Membrane stabilising drugs (a) Ajmaline, Cibenzoline (Cifenline),* Disopyramide, Procainamide, Quinidine (b) Aprindine, Lidocaine, Mexiletine, Tocainide (c) Flecainide, Propafenone Class I, but not easily fitting above subgroups – Moracizine

Class II: Beta blocker activity Atenolol,Bretylium,† Propranolol

Class III: Inhibitors of depolarisation Amiodarone,Azimilide, Bretylium,† Cibenzoline (Cifenline),* Dofetilide, Dronedarone, Ibutilide, Sotalol

Class IV: Calcium-channel blocker activity Cibenzoline (Cifenline),* Diltiazem,Verapamil

(See reference number *)Cibenzoline has class Ia,and also some class III and IV activity

Table 1 Antiarrhythmics (modified Vaughan Williams classification)
Class I: Membrane stabilising drugs (a) Ajmaline, Cibenzoline (Cifenline),* Disopyramide, Procainamide, Quinidine (b) Aprindine, Lidocaine, Mexiletine, Tocainide (c) Flecainide, Propafenone Class I, but not easily fitting the above subgroups – Moracizine
Class II: Beta blocker activity Atenolol, Bretylium,† Propranolol
Class III: Inhibitors of depolarisation Amiodarone, Azimilide, Bretylium,† Cibenzoline (Cifenline),* Dofetilide, Dronedarone, Ibutilide, Sotalol
Class IV: Calcium-channel blocker activity Cibenzoline (Cifenline),* Diltiazem, Verapamil
Drugs not fitting into this classification Adenosine

Table 2 Antiarrhythmics (modified Vaughan Williams classification)
Class I: Membrane stabilising drugs (a) Ajmaline, Cibenzoline (Cifenline),* Disopyramide, Procainamide, Quinidine (b) Aprindine, Lidocaine, Mexiletine, Tocainide (c) Flecainide, Propafenone Class I, but not easily fitting the above subgroups – Moracizine
Class II: Beta blocker activity Atenolol, Bretylium,† Propranolol
Class III: Inhibitors of depolarisation Amiodarone, Azimilide, Bretylium,† Cibenzoline (Cifenline),* Dofetilide, Dronedarone, Ibutilide, Sotalol
Class IV: Calcium-channel blocker activity Cibenzoline (Cifenline),* Diltiazem, Verapamil
Drugs not fitting into this classification Adenosine