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Effects of calcium channel blocker overdose-induced toxicity in the conscious dog
J M Schoffstall1, W H Spivey, L M Gambone
1Department of Emergency Medicine, Medical College of Pennsylvania, Philadelphia 19129.
Study 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.
Design:
Nonblinded, controlled animal study.
Setting:
Research laboratory of a large pharmaceutical company.
Type Of Participants:
Nineteen healthy mongrel dogs obtained from a commercial supplier.
Interventions:
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.
Measurements And Main 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.