Possible Interaction: Diltiazem and Epinephrine

“Platelet aggregation and ATP release induced by adrenaline and ADP and ADP induced platelet thromboxane A2 generation were significantly inhibited (P less than 0.05) by either diltiazem or propranolol, although propranolol tended to have greater inhibitory effects on platelet function than diltiazem that did not reach statistical significance.”

“In ganglion-blocked SHR, the smaller dose of diltiazem antagonized by 40 and 80% the pressor effects of norepinephrine and B-HT 920, respectively, but failed to change the vasoconstrictor responses of phenylephrine, epinephrine , or vasopressin, which were, however, reduced by the higher dose of diltiazem.”

“This suggests that DL significantly increases the threshold for the induction of arrhythmias associated with epinephrine and halothane.”

“The synergistic interaction of …-5 microM) and epinephrine (0.5-2 microM) was inhibited by alpha2-adrenoceptor …; IC50= 0.4 microM), calcium channel blockers (verapamil and diltiazem with IC50 of 10 and 48 mM, respectively), PLC inhibitor (U73122; … microM) and nitric oxide (NO) donor, SNAP (IC50=1.6 microM)).”

“The SNAP, diltiazem and verapamil inhibited the platelet aggregation induced by A23187 and epinephrine with IC50 value of 0.5 microM, 50 microM and 22 microM respectively.”

“Results showed that diltiazem inhibits platelet aggregation induced by ADP, arginine vasopressin, adrenaline , collagen, Na arachidonate, thrombin and phorbol ester PMA in a dose-dependent way.”

“ Diltiazem and verapamil inhibited aggregation caused by adrenaline 5 microM and collagen 2 micrograms/ml, but only at concentrations far in excess of those seen in clinical use.”

“ Diltiazem , in therapeutic concentrations (50–200 ng/ml), inhibited human platelet activation induced by cumulative sub-threshold concentrations of calcium ionophore A 23187 plus ADP or epinephrine.”

“However, platelet activation induced by cumulative effects of ADP plus ephinephrine was inhibited by diltiazem only in very high concentrations (>5 μg/ml).”

“ Diltiazem inhibited platelet aggregation induced by 2 … ADP or 5.5 microM epinephrine alone at 5 and 50 micrograms/ml (11.1 and 111 microM), respectively, and that induced by threshold … of ADP or epinephrine at 0.2 to 1.0 micrograms/ml (0.4 to 2.2 microM).”

“On the basis of these data, we conclude that (1) Ca++ flux across the platelet membrane stimulates platelet activity of subthreshold concentrations of ADP or epinephrine and (2) diltiazem in therapeutic concentrations reduces platelet activation induced by ionophore A23187 plus ADP or epinephrine , most likely by inhibiting Ca++ flux.”

“Platelet TXA2 generation stimulated by either ADP or epinephrine alone was inhibited by diltiazem in concentrations above the clinically achieved range (0.05 to 0.2 micrograms/ml, 0.1 to 0.4 microM).”

“The development of fatal arrhythmias, mainly ventricular tachyarrhythmias, occurred at significantly (P less than 0.05) greater concentrations of epinephrine with diltiazem , 50 and 10 micrograms/kg, 225 +/- 5 and 183 +/- 13 micrograms/kg, respectively, compared to controls, 131 +/- 15 micrograms/kg.”

“The onset of ventricular arrhythmias, … 0.05) greater dose of epinephrine, … diltiazem , compared to the control group and in a dose-dependent manner, with the mean (+/- 1 SEM) dose of epinephrine …/kg in the groups treated with 50 and 10 micrograms/kg of diltiazem and the control groups, respectively.”