Reversal of propranolol blockade of adrenergic receptors and related toxicity with drugs that increase cyclic AMP.
An overdose of propranolol, a widely used nonselective beta-adrenergic receptor blocking agent, can result in hypotension and bradycardia leading to irreversible shock and death. In addition, the blockade of adrenergic receptors can lead to alterations in neurotransmitter receptors resulting in the interruption of the activity of other second messengers and the ultimate cellular responses. In the present experiment, three agents, aminophylline, amrinone, and forskolin were tested in an attempt to reverse the potential lethal effects of a propranolol overdose in dogs. Twenty-two anesthetized beagle dogs were given a 10-min infusion of propranolol at a dose of 1 mg/kg/min. Six of the dogs, treated only with intravenous saline, served as controls. Within 15-30 min all six control dogs exhibited profound hypotension and severe bradycardia that led to cardiogenic shock and death. Seven dogs were treated with intravenous aminophylline 20 mg/kg 5 min after the end of the propranolol infusion. Within 10-15 min heart rate and systemic arterial blood pressure returned to near control levels, and all seven dogs survived. Intravenous amrinone (2-3 mg/kg) given to five dogs, and forskolin (1-2 mg/kg) given to four dogs, also increased heart rate and systemic arterial blood pressure but the recovery of these parameters was appreciably slower than that seen with aminophylline. All of these animals also survived with no apparent adverse effects. Histopathologic evaluation of the hearts of the dogs treated with aminophylline showed less damage (vacuolization, inflammation, hemorrhage) than the hearts from animals given propranolol alone. Results of this study showed that these three drugs, all of which increase cyclic AMP, are capable of reversing the otherwise lethal effects of a propranolol overdose in dogs.
Whitehurst
V E
VE
Division of Pulmonary Drug Products, Food and Drug Administration, Rockville, Maryland 20857, USA. Whitehurst@CDER.FDA.GOV
Vick
J A
JA
Alleva
F R
FR
Zhang
J
J
Joseph
X
X
Balazs
T
T
D000262:Adenylyl Cyclases / Q000378:metabolism; D018674:Adrenergic Antagonists / Q000633:toxicity*; D000628:Aminophylline / Q000494:pharmacology; D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011433:Propranolol / Q000633:toxicity*; D012119:Respiration / Q000187:drug effects
D018674:Adrenergic Antagonists; D010726:Phosphodiesterase Inhibitors; D005576:Colforsin; D000628:Aminophylline; D011433:Propranolol; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000676:Amrinone