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The purpose of this study was to compare ganglionic blockade with trimethaphan (TMP) and an alternative drug strategy using combined muscarinic antagonist (glycopyrrolate, GLY) and alpha-2 agonist (dexmedetomidine, DEX). Protocol 1: incremental phenylephrine was administered during control and combined GLY-DEX, or control and TMP on two control combined GLY and DEX or TMP infusion on two randomized days. Protocol 2: muscle sympathetic nerve activity (MSNA) and the baroreflex MSNA relationship was determined before and after GLY-DEX. Blood pressure was higher with GLY-DEX (99+/-3 mm Hg) and lower with TMP (78+/-3 mm Hg) relative to control (GLY-DEX: 90+/-2 mm Hg; TMP: 91+/-2 mm Hg; P<0.05). Incremental phenylephrine increased pressure during GLY-DEX (P<0.01 vs control) and TMP (P<0.01 vs control) to a similar degree. Both GLY-DEX and TMP infusion inhibited norepinephrine release (P<0.01 vs control). GLY-DEX inhibited baseline MSNA (P<0.05) and baroreflex changes in MSNA (P<0.01). We conclude that the GLY-DEX alternative drug strategy can be used as a reasonable alternative to pharmacologic ganglionic blockade to examine autonomic cardiovascular control.

The pharmacokinetics of verapamil were studied in patients with renal failure who were undergoing maintenance hemodialysis and in normal subjects after an IV infusion of 10 mg and a single oral dose of 120 mg. Plasma levels of verapamil and its active metabolite, norverapamil, were analyzed by a sensitive and specific HPLC procedure. Severe renal failure requiring hemodialysis did not change the time course of verapamil and norverapamil plasma concentrations after either the IV or oral dose. The terminal elimination rate constant, clearance, volume of distribution, and bioavailability of verapamil were not significantly different between the two groups of subjects. In addition, the apparent maximal plasma concentration, terminal elimination rate constant, and area under the curve for norverapamil were similar in patients with renal failure and normal subjects. The study showed that the plasma disposition of verapamil and norverapamil was not affected in patients with impaired renal function. Furthermore, this study does not indicate that any change in dosage is necessary when single doses of verapamil are administered to patients with renal failure.

Midodrine is an orally active adrenergic agonist useful in the treatment of hypotension. We have investigated the pharmacodynamics of its active metabolite after oral midodrine therapy in nine patients with severe orthostatic hypotension. Peak plasma levels of the metabolite were reached in 60 to 90 minutes and ranged from 25 to 56 ng/ml. The mean values for distribution volume, plasma clearance, and t1/2 were 4.0 L/kg, 23 ml/min/kg, and 2.1 hours, respectively. Heart rate increased after 5 to 10 mg doses and the increases were statistically significant (P less than 0.05) at 120 minutes. An apparent increase in blood pressure was not statistically significant. The patients said that they felt better.