Effects of isradipine on intravenous cocaine-induced cardiovascular response: a pilot study

Abstract

We examined the eects of isradipine, a dihydropyridine-class calcium channel antagonist, and eective antihypertensive medication on the pressor eects of cocaine on cardiac function. Using continuous non-invasive cardiovascular monitoring of heart rate, blood pressure, electrocardiographic recordings, and peripheral oxygen saturation, six healthy cocaine addicts received the following treatments in blinded, crossover fashion: (a) placebo; (b) intravenous cocaine (0 . 325 mg/kg iv), and (c) isradipine (10 mg pXoX cocaine. While cocaine-taking was associated with a small increase in blood pressure, this eect was not signi®cantly aected by isradipine. Isradipine pretreatment was, however, associated with a signi®cant re¯ex rise in heart rate following cocaine. Cocaine administration with or without isradipine produced no clinically signi®cant abnormalities of rhythm or conduction on the electrocardiogram and on peripheral oxygen saturation. While these results should be considered preliminary, they do suggest that this isradipine dose and/or dosing strategy does not have a clinically signi®cant cardioprotective eect during cocaine-taking.

Effects of Isradipine, a Dihydropyridine-Class Calcium Channel Antagonist, on D-Methamphetamine-Induced Cognitive and Physiological Changes in Humans

“…Isradipine's anti-hypertensive effect is presumably the result of its anti-DA actions. Interestingly, isradipine's relatively greater anti-hypertensive effect following d-methamphetamine in this experiment, compared with our previous work on cocaine (Johnson et al 1999), was probably a function of the relatively higher dose (10 mg, orally vs. approximately 15 mg for a 70 kg individual) rather than a differential pharmacological effect. We did, however, consider the possibility that isradipine's apparently exaggerated pharmacological effect may be mediated by d-methamphetamine's complex interactions with N-methyl-D-Aspartate receptors; however, these effects have primarily been described in neural tissue (Abekawa et al 1997;Snyder 1992).…”

“…As predicted, isradipine was effective at reducing the hypertensive effects of d-methamphetamine, particularly diastolic pressure. D-methamphetamine's hypertensive effects appear more pronounced than those we obtained with cocaine (Johnson et al 1999), presumably because it has a greater duration of action on increasing monoamine levels. Isradipine's anti-hypertensive effect is presumably the result of its anti-DA actions.…”

Effects of repeated-dose isradipine on the abuse liability of cocaine.

“…However, the acute immediate-release doses (15 mg) in addition to the repeated sustained-release isradipine doses (30 mg) exceeded substantially the recommended dose for the approved antihypertensive indication for isradipine (Physicians' Desk Reference (PDR), 2002). Furthermore, this dosing strategy would be expected to achieve much higher blood levels than the immediate-release regimens (10 mg) previously shown to attenuate cocaine-induced brain ischemia (Johnson et al, 1998(Johnson et al, , 2001 and pressor effects (Johnson et al, 1999) in cocaine-dependent volunteers. Given the 8-hr half-life of isradipine and the fact that it is formulated in a sustained-release preparation (PDR, 2002), the 4 days of repeated dosing would have achieved steady-state levels, and the acute dosing with immediate-release isradipine before the cocaine infusion would have added considerably to those blood levels.…”

“…Our group has conducted several previous studies with isradipine (Johnson, Devous, Ruiz, & Ait-Daoud, 2001). We found that acute doses of 10-mg immediate-release isradipine counteracted cocaine-induced reductions in brain blood flow as measured by single photon emission computerized tomography (Johnson et al, 1998) and reduced the pressor effects of cocaine (Johnson et al, 1999)—actions that also may be partially mediated through monoamine mechanisms. Gottschalk and Kosten (2002) replicated these results.…”

“…Unfortunately, the sustained-release isradipine doses did not attenuate the subjective or reinforcing effects of cocaine. Given the positive results with isradipine in preclinical studies and our previous studies using immediate-release isradipine (Johnson et al, 1998(Johnson et al, , 1999, we speculated that the sustained-release doses may not have achieved high enough blood levels (Holmes & Kutz, 1993) and that the immediate-release formulation may be necessary to achieve the desired effects. Thus, the current study sought to maximize the isradipine dosing regimen through a combination of repeated doses of sustained-release isradipine (30 mg) and acute doses of the immediate-release preparation (15 mg).…”