Effects of calcium channel blocker overdose-induced toxicity in the conscious dog.
OBJECTIVE
To evaluate the effects of nifedipine, diltiazem, and verapamil overdose on systemic hemodynamics and blood flows to the coronary, superior mesenteric, renal, and iliac arteries in the unanesthetized dog.


METHODS
Nonblinded, controlled animal study.


METHODS
Research laboratory of a large pharmaceutical company.


METHODS
Nineteen healthy mongrel dogs obtained from a commercial supplier.


METHODS
Under general anesthesia, flow probes were placed about the ascending aorta, circumflex coronary, superior mesenteric, renal, and iliac arteries; a micromanometer was implanted into the tip of the left ventricle; and a catheter was inserted into the descending aorta. Experiments were performed after a recovery period of at least two weeks.


RESULTS
Arterial blood pressure, heart rate, cardiac output, left ventricular pressure, and regional blood flows were measured prior to drug administration, and after 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg IV administration of the study drugs. Dogs receiving diltiazem or verapamil also received a dose of 10.0 mg/kg. When the blood pressure had been reduced from baseline by 30%, 1.43 mg/kg nifedipine IV (six dogs) decreased total peripheral resistance by 51%, increased cardiac output by 35%, and increased heart rate by 132%. Coronary blood flow and iliac blood flow increased 93% and 45%, respectively, but mesenteric blood flow and renal blood flow were not significantly altered. Diltiazem (eight) and verapamil (seven) at equivasodepressor doses (1.43 to 4.43 mg/kg) caused less peripheral vasodilation and reflex tachycardia. At severely toxic levels when arterial blood pressure fell by 50%, all three drugs decreased cardiac output. Nifedipine still increased heart rate. Diltiazem and verapamil caused high-grade atrioventricular block, resulting in bradycardia. All three drugs caused a redistribution of cardiac output favoring the coronary bed over the other beds.


CONCLUSIONS
In the conscious dog, calcium channel blocker-induced hypotension at the moderate level is associated with disparate effects on systemic hemodynamics, probably resulting from differential reflex sympathetic activation. However, at a more severe level, their toxic effects are similar and manifested predominantly by their actions on the slow calcium channel.
Department of Emergency Medicine, Medical College of Pennsylvania, Philadelphia 19129.
J M
JM
Schoffstall
W H
WH
Spivey
L M
LM
Gambone
R P
RP
Shaw
S P
SP
Sit
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004110:Diltiazem / Q000633:toxicity*; D004285:Dogs; D062787:Drug Overdose; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D008297:Male; D009543:Nifedipine / Q000633:toxicity*; D014700:Verapamil / Q000633:toxicity*
D014700:Verapamil; D004110:Diltiazem; D009543:Nifedipine