Combined effects of cocaine and nicotine on cardiovascular performance in a canine model.
BACKGROUND
With the proliferation of cocaine abuse, increased incidence of catastrophic cardiovascular events such as angina pectoris, myocardial infarction, ventricular arrhythmias, or sudden death are reported. Many of these patients also smoke cigarettes before and after cocaine use, leading to a high frequency of simultaneous exposure to both drugs. Cocaine's and nicotine's independent effects on cardiodynamics are well documented, but combined effects of both on complete cardiovascular hemodynamics remain unknown.


OBJECTIVE
The study aimed to determine whether these effects are additive, synergistic, or antagonistic and was therefore designed to investigate the cardiovascular changes produced as a result of combined administration of cocaine and nicotine in a canine model.


METHODS
Initially, in phase 1, 30 experiments were performed to study the dose-response curve of both drugs. In phase II and III, 12 dogs were subjected to 30 experiments. In phase II, cocaine was given intravenously (IV) followed by nicotine. In phase III, sequence of drug administration was reversed to study the effects on hemodynamics and coronary artery blood flow reserve.


RESULTS
Hemodynamic parameters observed were Phase I: Dose-response curve established the IV bolus dose of cocaine 2 mg/kg and nicotine 50 microg/kg. Phase II: Cocaine increased heart rate, blood pressure, and dP/dt, but nicotine administration after cocaine produced marked significant synergistic excitatory effects: dP/dt increased from 1,810 +/- 210 to 6,300 +/- 460 (p < 0.003). Phase III: Nicotine significantly increased heart rate, mean arterial pressures, left ventricular end-diastolic pressure, pulmonary artery, pulmonary capillary wedge, and right atrial pressures. Nicotine increased dP/dt (1,810 +/- 192 to 5,000 +/- 160 mmHg/s; p < 0.004). These excitatory effects of nicotine were attenuated by cocaine when administered as a second drug (dP/dt decreased to 1,925 +/- 144 from 5,000 +/- 160 mmHg/s;p < 0.004).


CONCLUSIONS
Cocaine, when administered alone, caused increase in heart rate, blood pressure, and dP/dt, but nicotine showed a significant increase in all the hemodynamic parameters. Both drugs reduced coronary blood flow reserve. In combination, cocaine plus nicotine administration had synergistic excitatory effects in dogs. A reversed drug combination, that is, nicotine plus cocaine, attenuated the excitatory effects of nicotine.
Mehta
M C
MC
Department of Medicine, Section of Cardiology, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, Morgantown 26506-9157, USA.
Jain
A C
AC
Billie
M D
MD
D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D004285:Dogs; D004338:Drug Combinations; D005731:Ganglionic Stimulants / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D008955:Models, Cardiovascular; D009538:Nicotine / Q000494:pharmacology*; D019966:Substance-Related Disorders; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D004338:Drug Combinations; D005731:Ganglionic Stimulants; D014662:Vasoconstrictor Agents; D009538:Nicotine; D003042:Cocaine