Comparison of cocaine and Na+ channel blockers on cardio-respiratory function in the rabbit.

The cardio-respiratory effects of cocaine were compared to various Na+ channel blocking Class I antiarrhythmics. Anesthetized rabbits were treated with various doses of either cocaine, quinidine, procainamide, lidocaine or flecainide. Cocaine produced clear decreases in blood pressure and heart rate. None of the other sodium channel blockers produced any change in blood pressure, and heart rate was decreased only slightly by procainamide and lidocaine. Cocaine produced larger increases in QRS duration than were observed for the four sodium channel blockers. All five drugs produced comparable increases in respiratory rate. Separate rabbits were pretreated with either the alpha-adrenoceptor antagonist phentolamine or the beta-adrenoceptor antagonist propranolol prior to cocaine. Phentolamine attenuated the blood pressure decrease following cocaine and propranolol attenuated the heart rate decrease following cocaine. These results suggest that the sodium channel blocking properties contribute only minimally to the overall effects of cocaine on blood pressure and heart rate. Further, the large effect of cocaine on QRS duration suggests that cocaine may act at sodium channels in a manner different from the other drugs. This unique effect of cocaine may contribute to the sudden death associated with cocaine use in some individuals.

Pharmacological mechanisms in cocaine's cardiovascular effects.

The squirrel monkey is a reliable model for the cardiovascular effects of cocaine in that it mimics the human response to cocaine; low to moderate doses of cocaine produce a sustained pressor effect and tachycardia. Pretreatment experiments have indicated the importance of alpha-1 and beta-1 adrenoceptor mechanisms in mediating the pressor and tachycardiac effects of cocaine, respectively. Little support for a role of dopaminergic mechanisms in the hemodynamic effects of cocaine has been found. Toxicity to cocaine is often observed hours after its administration, pointing to a potential role of the cocaine metabolites. Studies on the direct effects of a variety of cocaine metabolites indicate that their cardiovascular effects do not necessarily mimic those produced by cocaine, and therefore these differing effects of the metabolites should be considered when evaluating the cardiovascular toxicity of cocaine. Further, as these metabolites are present in the body for long periods of time, these results suggest a role of the metabolites in producing toxicity long after cocaine administration. Finally, studies using both dopaminergic and calcium channel antagonists indicate that the pharmacological mechanisms involved in the cardiovascular effects of cocaine are not the same as those involved in its behavioral effects.

Sympathetic nervous system mediated cardiovascular effects of cocaine are primarily due to a peripheral site of action of the drug.

Currently, augmentation of sympathetic nervous system function produced by cocaine is thought to be due primarily to stimulation of sympathetic centers in the brain (central effect) and to inhibition of catecholamine uptake into postganglionic sympathetic nerve terminals (peripheral effect). In this review of our work, we present the following evidence that cocaine-induced changes in cardiovascular function, particularly those that peak within 1 to 5 min after an i.v. bolus injection of the drug, are due to a peripheral effect of the drug: (1) In both dogs and cats, cocaine potentiates the tachycardiac effect of neurally-released and injected norepinephrine (NE). The time course of action and dosage range of cocaine that produces potentiation follows that which increases blood pressure (BP), heart rate (HR), rate-pressure product and coronary vasoconstriction. (2) Cocaine given in i.v. doses that increase BP in decerebrate cats (0.25-1.0 mg/kg) has no significant effect on directly monitored spontaneous cardiac sympathetic nerve activity (SNA). In fact, higher doses of cocaine (2-4 mg/kg, i.v.) consistently inhibit preganglionic cardiac and splanchnic nerve activity. (3) Cocaine (0.1-1.0 mg) administered directly into the blood supply of the hindbrain via the vertebral artery produces no increase in BP, HR or SNA in cats; instead, decreases in BP and sympathetic activity occur. The same dose (1 mg), injected i.v., does not depress BP or SNA. In addition, cocaine injected into the forebrain via the carotid artery or into the cerebral ventricles (0.1-1.0 mg) has very little effect on BP. Our results indicate that there is no significant excitatory effect of cocaine on CNS sympathetic centers, and that the sympathomimetic effects of cocaine on the cardiovascular system are likely to be mediated at peripheral sites.

Effects of cocaine, cocaine metabolites and cocaine pyrolysis products on the hindbrain cardiac and respiratory centers of the rabbit.

Hemodynamic and respiratory effects of vertebral artery or i.v. administration of cocaine, cocaine metabolites and cocaine pyrolysis products were measured in anesthetized rabbits. Vertebral artery administration of 1 mg of cocaine produced decreases in blood pressure and heart rate and respiratory arrest. Cocaethylene (1 mg), a cocaine metabolite produced following co-administration of cocaine and ethanol, had comparable effects except that the respiratory arrest following cocaethylene had a longer duration of action than did cocaine. A decrease in blood pressure was also observed following 1 mg of norcocaine; however, unlike cocaine, norcocaine did not affect respiration. Acute tolerance was not observed to any of the effects of 1 mg of cocaine, cocaethylene or norcocaine following vertebral artery administration. None of these compounds had significant effects following i.v. administration of the same dose. The cocaine metabolites benzoylecgonine and ecgonine methyl ester were without effect by either route in doses up to 3 mg. In contrast to cocaine, the cocaine pyrolysis products anhydroecgonine methyl ester (3 mg) and noranhydroecgonine methyl ester (3 mg) produced similar effects via both routes of administration. Both compounds produced decreases in blood pressure and heart rate and an increase in respiratory rate. Anhydroecgonine ethyl ester (3 mg), a metabolite hypothetically formed from the cocaine pyrolysis product in individuals co-administering ethanol, had effects similar to the other pyrolysis products, although its effects were not as prominent via the i.v. route of administration. Acute tolerance was observed upon administration of the cocaine pyrolysis products. These results indicate that the cocaine pyrolysis products do not share a common mechanism of action with either cocaine or the cocaine metabolites.

Comparison of the effects of cocaine and its metabolites on cardiovascular function in anesthetized rats.

Hemodynamic and cardiac-electrophysiologic effects of cocaine and its metabolites were measured in 18 groups (n = 6 each) of anesthetized, artificially ventilated rats during continuous intravenous (i.v.) infusions at three different doses (0.15, 0.45, and 1.5 mg/kg/min). At the highest dose, cocaine decreased blood pressure (BP) and heart rate (HR), while QRS duration, an index of cocaine's local anesthetic effect, was increased. Cocaethylene, a metabolite produced after coadministration of cocaine and ethanol, had effects comparable to those of cocaine. The cocaine metabolite norcocaine produced a decrease in BP at the lower dose that reversed to a small increase at the higher dose. The highest dose of norcocaine clearly decreased HR and increased QRS duration. The increases in QRS duration observed for cocaine, cocaethylene, and norcocaine were reversed by sodium bicarbonate. The cocaine metabolites benzoylecgonine and ecgonine methyl ester increased BP at the higher doses without affecting either HR or QRS duration. These results suggest that the spectrum of effects produced by cocaine are not necessarily mimicked by its metabolites. In particular, accumulation of the persistent, active metabolites benzoylecgonine and ecgonine methyl ester may contribute to delayed-onset, cocaine-related toxicity.

Cocaine acts in the central nervous system to inhibit sympathetic neural activity.

Cocaine was administered i.v. to decerebrate cats while monitoring cardiac preganglionic sympathetic nerve activity (SNA), arterial blood pressure (BP) and heart rate (HR). Cocaine, 4 mg/kg i.v., reduced SNA by 55 +/- 6%, but did not significantly affect BP or HR. Cocaine, in doses that were ineffective by the i.v. route, was administered into the vertebral artery and produced decreases in SNA, BP and HR in anesthetized cats. Administration of cocaine into the carotid artery was without effect. Topical administration of cocaine to the intermediate area of the ventrolateral medullary surface (25 micrograms/side) evoked hypotension and bradycardia. Nisoxetine, an inhibitor of norepinephrine uptake, applied bilaterally to the intermediate area (30 micrograms/side) exerted a similar hypotensive effect. Lidocaine administered in doses equivalent to those of cocaine had no significant effect on SNA when given i.v. or on BP when given into the vertebral artery. These results indicate that cocaine inhibits central sympathetic outflow and that the site of action appears to be in the hindbrain at a site that is reached by placement of the drug at the intermediate area of the ventrolateral medulla. The data also indicate that the mechanism of action of cocaine to inhibit sympathetic outflow may be unrelated to its local anesthetic action and may involve inhibition of catecholamine uptake in the ventrolateral medulla.