Posted by John B (22.214.171.124) on March 17, 2001 at 07:40:37:
American Journal of Health-System Pharmacy
Verapamil Intoxication After Substitution of Immediate-Release for Extended-Release Verapamil
Patrice Laberge, Pierre Martineau, Herawaty Sebajang, and Guy Lalonde
[Am J Health-Syst Pharm 58(05):402-405, 2001. © 2001 ASHP, Inc.]
Verapamil is a phenylalkylamine calcium-channel antagonist used mainly in cardiovascular disorders, such as hypertension, coronary artery disease, and supraventricular arrhythmias.[1-4] In addition, by virtue of its vasodilatory effects on cerebral arteries and possibly its modulation of central neurotransmitters, verapamil is used for the prophylaxis of migraine and cluster headaches.[5-7]
Because the formulation of verapamil may play a role in the drug's complex pharmacokinetics, one formulation of verapamil cannot be safely substituted for another. This report describes a case in which inappropriate substitution of one verapamil formulation for another had harmful consequences and briefly reviews verapamil's pharmacokinetics and pharmacodynamics.
A 51-year-old, 86-kg, white man came to the emergency room with severe bradycardia, diaphoresis, and weakness. His medical Verapamil intoxication after substitution of immediate-release for extended-release verapamil history was significant only for a 30- year history of cluster headaches, for which he was currently taking lithium carbonate 300 mg and extended-release verapamil hydrochloride 240 mg (Isoptin SR, Knoll), each three times daily. The cluster headaches were well controlled by this regimen, with few adverse effects other than slight ankle edema.
On the day of his admission, the patient took his usual morning doses of lithium and extended-release verapamil. Because his supply of verapamil was then exhausted, he went to his pharmacy for a refill. When he complained about the high cost of Isoptin SR, the pharmacist recommended and dispensed an equivalent dosage of generic immediate-release verapamil hydrochloride (two 120- mg tablets three times daily) instead of the more expensive brand-name extended-release formulation. During the afternoon, about 30 minutes after taking his first dose of immediate- release verapamil, the patient rapidly became weak, dizzy, and diaphoretic. Paramedics found him with severe bradycardia (23 beats/min) and hypotension (Korotkoff sounds inaudible). The patient remained conscious but was unable to move. After he was given atropine sulfate 2 mg i.v., his blood pressure was 85/48 mm Hg, his heart rate was 60 beats/ min, and his respiratory rate was 20 breaths/min.
When he arrived at the emergency room, the patient's blood pressure was 75/50 mm Hg and his heart rate was 60 beats/min. The first electro-cardiogram (ECG) showed no P waves, QRS complexes with a left-bundle- branch-block morphology and a duration of 164 msec, and right axis deviation (110°). This was interpreted as an accelerated idioventricular rhythm, although a junctional tachycardia with aberrant conduction could not be ruled out. The blood pressure increased to 90/55 mm Hg after rapid infusion of 1 L of 0.9% sodium chloride injection. Thereafter, blood pressure remained stable in the range of 90-100/50-60 mm Hg, and the resting pulse rate stayed between 50 and 80 beats/min. The results of blood tests (complete blood count, electrolytes, aspartate transaminase, alanine transaminase, and thyroid-stimulating hormone) were all within the normal ranges. The serum lithium concentration was 0.58 mmol/ L (therapeutic range, 0.60-1.20 mmol/ L). Blood verapamil levels were not measured because this test is not routinely performed at our institution.
The provisional diagnosis was verapamil intoxication. The patient was admitted to the coronary care unit for monitoring. No further treatment was deemed necessary. A thorough medication history, performed by the clinical pharmacist and confirmed with the community pharmacist, uncovered the substitution of immediate- release for extended-release verapamil. The following morning, the ECG showed sinus bradycardia (43 beats/min), left axis deviation (-40°), slight widening of the QRS complex (90-100 msec), and notching of the S waves in leads II, III, aVF, V5, and V6. T waves were flattened or slightly inverted in leads V1 to V6. This was interpreted as a slight intraventricular conduction defect with nonspecific T-wave abnormalities.
It was decided to restart the patient's usual medication consisting of lithium carbonate 300 mg and extended- release verapamil hydrochloride 240 mg three times daily, with continuous monitoring. No further dysrhythmias were observed, and the patient successfully underwent a treadmill test performed to rule out ischemia as the cause of the bradyarrhythmia. The patient remained clinically stable throughout the hospital stay. Subsequent ECGs recorded on days 3 and 5 remained unchanged, showing the same intraventricular conduction defect with non-specific T-wave abnormalities. The patient was advised to continue taking his usual medication and was thoroughly counseled about differences between verapamil formulations and about therapeutic substitution. The community pharmacist was informed about the situation.
Prophylaxis of cluster headaches, a refractory type of migraine, may require daily doses of verapamil hydrochloride as high as 1200 mg. The lowest effective dose should be used, and the patient should be closely monitored for adverse effects. Use of the extended-release formulation of verapamil is practical; it often allows for once-daily administration and is better tolerated than the immediate-release formulation. In the case of our patient, because of the high dosage of verapamil required it was first decided to administer the extended-release formulation in three divided doses to avoid adverse effects related to the peak plasma concentration of the drug. The dosage was adjusted upward to 1080 mg/day because of a suboptimal clinical response but was then decreased to 720 mg/day when ankle edema developed. Until the day the patient was admitted, he had never had symptoms of bradycardia, syncope, or other cardiovascular adverse effects. Why did a simple switch to the immediate-release formulation prove harmful almost immediately after the first dose? To answer this question, it is necessary to review the complex pharmacokinetics and pharmacodynamics of verapamil.
Verapamil possesses a chiral carbon and is marketed as a racemic mixture of R- and S-stereoisomers.[8,9] In humans, both isomers share qualitatively similar negative dromotropic and chronotropic effects on the sinoatrial and atrioventricular nodes, but the S-stereoisomer is 10- 20 times more potent than the R with respect to these effects. Hence, the S-stereoisomer determines the negative dromotropic effects of verapamil, while the R-stereoisomer is of minor importance.[3,4,10,11] Furthermore, in a dog model, S-verapamil was 5, 15, and 2.5 times more potent than R-verapamil in terms of negative chronotropic, inotropic, and coronary vasodilatory properties, respectively. Verapamil's major plasma metabolite is the N-demethylated derivative norverapamil. Norverapamil, a chiral substance itself, is verapamil's most active biotransformation product and exerts approximately 10% of the electrophysiologic properties of the parent drug and 20% of its vasodilatory properties.[13,14] Hence, altering the relative proportions of verapamil stereoisomers in the blood could result in profound changes in the drug's pharmacodynamic effects.
Verapamil also undergoes extensive stereoselective first-pass hepatic metabolism.[8,15] S-verapamil is more rapidly metabolized than R-verapamil after oral administration, resulting in a lower bioavailability of the S-stereoisomer and a proportionally higher concentration of the R-stereoisomer in the systemic circulation (20% and 50%, respectively).[3,8,9,15] After oral administration of racemic verapamil, Vogelgesang et al. found that the peak plasma concentration (Cmax) and the area under the plasma-versus-time curve (AUC) of the R-stereoisomer were five times higher than those of the S-stereoisomer and that clearance of the S-stereoisomer was four to five times greater. The resulting plasma R/S ratio was 4.92, versus 2 after i.v. administration, indicating that S-verapamil is preferentially metabolized during the first pass through the liver. This explains why oral verapamil is less potent than i.v. verapamil, even at comparable total plasma concentrations, and why it takes more than a twofold to threefold increase in the blood concentration of orally administered racemic verapamil to achieve the same effect as with the i.v. formulation.[3,8,15,16] Moreover, the enzymes that metabolize verapamil in the liver become saturated at a lower concentration of S-verapamil than R-verapamil, indicating saturable and stereoselective metabolic pathways for both stereoisomers. Hence, the rate of absorption or the amount of verapamil delivered to the hepatic microsomes appears to be of particular importance in determining the R/S ratio and thus the therapeutic effects.
To test the hypothesis that the R/S ratio can be affected by the rate of oral input of racemic verapamil, Karim and Piergies  conducted a crossover study in which immediate-release and extended-release formulations were administered to 12 healthy volunteers. The subjects were randomly assigned to receive a single 240-mg dose of racemic verapamil hydrochloride as either formulation; after a washout period of seven days, they were given the other formulation. The protocol was designed to maximize the difference in input rates between formulations: the immediate-release formulation was administered after an overnight fast, and the extended- release formulation was given after a high-fat breakfast. The investigators observed that the R/S ratio depended on the rate of absorption and hence on the amount of verapamil presented to the liver. At a high input rate (immediate-release formulation) and a low input rate (extended-release formulation), mean R/S ratios at Cmax were 4.52 and 5.83, respectively (p < 0.01); this represented a 29% difference in R/S ratios between input rates. However, because Cmax is higher with the immediate-release formulation and S-verapamil is 10- 20 times more potent than R-verapamil, it is not surprising that this difference is also clinically significant. With the immediate-release formulation, a plot of PR-interval changes versus time had the same shape as the concentration-versus-time curve. However, the extended-release formulation lacked a concentration-to-effect relationship. This was attributed to the difference in oral input rates, to the concentration-related saturable first-pass hepatic metabolism, or both.
More recent studies have provided evidence of presystemic metabolism of verapamil in the gut wall.[17-19] This extrahepatic metabolic pathway proved to be modulated by external factors, such as dietary salt intake and drugs like rifampin, a potent inducer of gut wall metabolism.[17,19] This first-pass metabolism within the enterocytes appears to be saturable and selective for S-verapamil, but its importance to overall bioavailability is still unclear. Moreover, single-dose administration of grapefruit juice, an inhibitor of intestinal cytochrome P-450 isoenzyme 3A4, does not significantly alter the pharmacokinetics of short-acting verapamil.
Sinus bradycardia, atrioventricular node block, and junctional rhythms have been described in patients receiving lithium. However, lithium's contribution appears to have been of minimal importance because of the low serum concentrations measured on admission, the long-term coadministration with verapamil, and the rapid onset of symptoms after the ingestion of the immediate-release verapamil dose. Our patient's signs and symptoms were an extension of the pharmacodynamic properties of verapamil. Even though we were unable to find a literature report of a case of verapamil toxicity caused by using immediate- release verapamil in place of an extended-release formulation, our patient's symptoms were similar to those reported in other cases of mild verapamil intoxication. The fact that he was taking a high dose of extended- release verapamil three times daily placed him at risk for cardiac disturbances that perhaps would not have occurred with a lower dose or once- or twice-daily administration. Since no plasma verapamil concentrations were measured, it is difficult to determine exactly what happened. But the pharmacokinetic principles described provide a good explanation for the events in this case.
After a single dose of verapamil is given, the mean time to Cmax for most extended-release formulations is 4- 8.3 hours, compared with 1-2 hours for immediate-release verapamil. Thus, when our patient took his usual afternoon dose of extended-release verapamil six to eight hours after the morning dose, it can be assumed that the absorption of the first dose was still ongoing and that some degree of hepatic microsomal enzyme saturation existed. Because the absorption of extended-release verapamil is relatively slow, the effect of the first dose tends to decrease before the rate of absorption of the second dose increases -- maintaining a somewhat constant rate of input of verapamil into the liver. Since the afternoon dose consisted of immediate-release verapamil hydrochloride 240 mg, we can assume that a very high verapamil input was achieved shortly after ingestion, adding to the continuing absorption of the morning dose of extended- release verapamil. This oral bolus dose of racemic verapamil probably exceeded the capacity of the microsomal enzymes. Since metabolism of the S-stereoisomer becomes saturated at a lower input rate, more S-verapamil than R-verapamil reached the systemic circulation, resulting in an acute decline in the plasma R/S ratio and thus an increase in pharmacologic effects. In the study by Karim and Piergies,  the Cmax of S-verapamil was more than five times higher after a single dose of immediate-release verapamil hydrochloride 240 mg than after the same dose of extended-release verapamil (57.6 versus 11.3 ng/mL, respectively; p < 0.01). The increased bio-availability and blood concentration of the S-stereoisomer blunted both sinus and atrioventricular node activity and led to severe bradycardia with a ventricular escape rhythm. The fact that symptoms began very shortly (30 minutes) after ingestion of the first immediate-release dose is consistent with the rapid dissolution and absorption of the immediate-release formulation.
The inappropriate substitution of immediate-release oral verapamil for the extended-release formulation was associated with adverse cardiovascular effects consistent with verapamil toxicity.
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