Pharmacodynamics (PD) of sumatriptan (S) in nitroglycerin-(NTG) induced headache (HA)

Our objective was to study the PD effects of NTG & S on middle cerebral artery blood flow velocity (MCAv) & on HA scores. 10 normal male volunteers received IV NTG, titrated within 30 min to 0.5 μg/kg/min, continuing for 3 h; S, either 2 mg IV or 6 mg SC, was given at 0.5 h; serial serum samples were obtained & assayed (HPLC) for S; MCAv was repeatedly measured before, during & after the IV NTG, by transcranial doppler sonography; HA scores (0 to 10) were also obtained at the same times. A PK/PD model was fit to the data using iterative 2-stage analysis; model discrimination was by Akaike's Information Criterion. The median HA score prior to S was 3.5; S reduced the HA in 9/10 subjects (median score=0; p=0.03). NTG reduced MCAv by a median of 27%. The differential equation, defining the indirect-effects PD model fit to the MCAv data, was: d MCAv/dt = Rin·NE^N - kout·[1-Emax·C^H/(EC₅₀^H+C ^H)]·MCAv in which Rin is the zero order rate of production of MCAv, kout is the first order rate constant for decrease in MCAv, NE is the effect of the NTG IV on Rin, N is a switch for the NTG (N=0 while IV is off & N=1 while on), C is the serum concentrations of S, Emax is the maximum fractional S-induced decrease in kout, EC₅₀ is the C at 50% of Emax & H is Hill's constant. The model fit the C (r=0.99) & the MCAv (r=0.89) data well; mean (CV%) fitted PD parameters included: Rin (cm/min²) NE (%) Emax (%) EC₅₀ (μg/L) kout (min^-1) 40.4 (50) 24.8 (112) 95.3 (52) 10.8 (52) 0.0110 (47) A significant S-inducsd increase (median=21%, p=0.01) in MCAv suggests a constricting effect on the NTG-induced dilated MCA. These results suggest that the NTG HA model may have utility in studying the clinical pharmacology of abortive anti-migraine drugs.