Haemodynamic and pharmacokinetic evaluation of alfuzosin in man. A dose ranging study and comparison with prazosin
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In an open dose ranging study with random inclusion of placebo, alfuzosin (α1-adrenoceptor antagonist) 1, 2.5 and 5 mg was administered to 6 healthy volunteers, 3 of the volunteers received 10 mg alfuzosin.
Supine systolic blood (SBP) pressure was not reduced by alfuzosin although significant increases occurred in supine heart rate (HR) after 2.5 and 5 mg. In the standing position, SBP was reduced at 2 and 4 h with 5 mg alfuzosin; significant increases in HR occurred following 1, 2.5 and 5 mg at 2, 4, 6 and 8 h after administration. Exercise SBP was not reduced; diastolic blood pressure was significantly reduced at 4 and 6 h with 5 mg alfuzosin. More marked effects were seen in the 3 subjects who received 10 mg alfuzosin. After 1 and 5 mg, tmax ranged from 1–2 h; Cmax (4.1 to 20.8 ng · ml−1; AUC (0–24) 20 to 132 ng · ml−1 · h (1 and 5 mg respectively) increased progressively with dose indicating dose dependent kinetics; no significant changes occurred in the visual analogue scale for sedation.
A comparison of alfuzosin 5 mg, prazosin 1 mg and placebo each administered for 4 days, indicated that alfuzosin did not significantly reduce standing SBP on either Day 1 or Day 4; prazosin reduced SBP at 2 and 4 h on Day 1 and 6 h on Day 4 compared to placebo. Standing HR was increased by alfuzosin at 2 h on Day 1 and Day 4; increases occurred with prazosin at 2, 4, 6 and 8 h on Day 1 and 6 h on Day 4.
Supine plasma noradrenaline increased with alfuzosin and prazosin at 2 and 4 h on Days 1 and 4; the increases were not significantly different. The plasma elimination half-life (t1/2) for alfuzosin was 3.4 h and 3.1 h after acute and chronic administration; (t1/2) for prazosin was 2.6 and 2.9 h.
In conclusion alfuzosin causes small reductions in systolic blood pressure, accompanied by a dose dependent increase in heart rate in the supine and standing position and following exercise.
Key wordsalfuzosin prazosin alpha1-adrenoceptor antagonist noradrenaline pharmacokinetics pharmacodynamics healthy volunteers
- Algate DR, Waterfall JF (1978) Action of indoramin on pre- and post-synaptic adrenoceptors in pithed rats. J Pharm Pharmacol 30: 651–655Google Scholar
- Awan NA, Miller RR, Maxwell K, Mason DT (1977) Effects of prazosin on forearm resistance and capacitance vessels. Clin Pharmacol Ther 22: 79–84Google Scholar
- Bateman DN, Hobbs DC, Twomey TM, Stevens EA, Rawlins MD (1979) Prazosin pharmacokinetics and concentration effect. Eur J Clin Pharmacol 16: 177–181Google Scholar
- Boakes AJ, Prichard BNC, Teoh PC (1972) α-Adrenoceptor inhibition from indoramin in man. Br J Pharmacol 44: 378–379Google Scholar
- Cambridge D, Davey MJ, Massingham R (1977) Prazosin, a selective antagonist of post-synaptic α-adrenoceptors. Br J Pharmacol 59: 514Google Scholar
- Cavero I, Lefevre F, Roach AG (1977) Differential effects of prazosin on the pre- and post-synaptic adrenoceptors in the rat and dog. Br J Pharmacol 59: 469Google Scholar
- Cavero I, Francoise Lefevre-Borg, Manoury PH (1984a) Alfuzosin (SL77.499), a new antihypertensive agent with a peripheral site of action. 1. In vivo pharmacological studies. Br J Pharmacol 81: 13Google Scholar
- Cavero I, Anne-Marie Galzin, Langer SZ, Francoise Lefevre-Borg, Manoury PH, Carmen Pimoule (1984b) Alfuzosin (SL77.499), a new antihypertensive agent with a peripheral site of action. 2. In vitro pharmacological studies. Br J Pharmacol 81: 14Google Scholar
- Collier JG, Lorge RE, Robinson BF (1978) Comparison of effects of tolmesoxide (Px 71107), diazoxide, hydrallazine, prazosin, glyceryl trinitrate and sodium nitroprusside on forearm arteries and dorsal hand veins of man. Br J Clin Pharmacol 5: 35–44Google Scholar
- Coltart DJ (1981) Clinical pharmacological studies of indoramin in man. Br J Clin Pharmacol 12: 495–605Google Scholar
- Davey MJ (1976) The pharmacological basis for the use of α1-Adrenoceptor antagonists in the treatment of essential hypertension. Br J Clin Pharmacol 21: 55–85Google Scholar
- Davies IB, Guinebault P, Johnston ES, Seymour D, Sinclair AJ, Warrington SJ (1986) α-Adrenoceptor antagonism by alfuzosin in man: Effects on phenylephrine pressor dose-responses. Br J Clin Pharmacol 22: 231–232Google Scholar
- Deering AH, Riddell JG, Harron DWG, Shanks RG (1988) Effect of acute and chronic administration of indoramin on baroreceptor function and tremor in man. J Cardiovasc Pharmacol 11: 284–290Google Scholar
- Deering AH, Riddell JG, Harron DWG, Shanks RG (1986b) Effect of acute and chronic oral administration of alfuzosin on baroreceptor function and tremor in man. Acta Pharm Toxicol [Suppl 5]: Abstract 776Google Scholar
- Dynon MK, Jarrott B, Drummer O, Louis WJ (1980) Pharmacokinetics of prazosin in normotensive subjects after low oral doses. Clin Pharmacokinet 5: 583–590Google Scholar
- Faerchtein I, Roque AE, Katansky I, Campos JC, Puppin S (1976) A placebo-controlled trial of the alpha-blocker indoramin, the treatment of arterial hypertension. Curr Med Res Opin 3: 675–684Google Scholar
- Fitzgerald GA, Watkins J, Dollery CT (1981) Regulation of norepinephrine release by peripheral 2-receptor stimulation. Clin Pharmacol Ther 29: 160–167Google Scholar
- Graham RM, Thornell IR, Gain JM, Bnoli C, Oates HF, Stokes GS (1976) Prazosin: The first dose phenomenon. Br Med J 2: 1293–1294Google Scholar
- Guinebault P, Broquaire M, Cola Franceschi C, Thenot JP (1986) High performance liquid chromatographic determination of alfuzosin in biological fluids with fluorimetric detection and large-volume injection. J Chromatogr 353: 361–369Google Scholar
- Hobbs DC, Twomey TM, Palmer RF (1978) Pharmacokinetics of prazosin in man. J Clin Pharmacol 18: 402–406Google Scholar
- Kincaid-Smith P, Hua ASP, Myers JB, MacDonald I, Fang P (1976) Prazosin and hydralazine in the treatment of hypertension. Clin Sci Mol Med 51: 6175–6095Google Scholar
- Krstulovic AM, Dziedzie SW, Biertani-Dziedzie L, Dirico DE (1981) Plasma catecholamines in hypertension and phaechromocytoma determined using ionpair reversed-phase chromatography with amperometric detection. Investigation of the separation mechanism and clinical methodology. J Chromatogr 217: 523–537Google Scholar
- Lewis PJ, George CF, Dollery CT (1973) Clinical evaluation of indoramin, a new anti-hypertensive agent. Eur J Clin Pharmacol 6: 211–216Google Scholar
- Nicholls DP, Harron DWG, Shanks RG (1983) Cardiovascular effects of indoramin in man — a dose ranging study. Br J Clin Pharmacol 15: 31–36Google Scholar
- Nicholls DP, O'Connor PC, Harron DWG, Leahey WJ, Shanks RG (1984) Differential blockade of α-adrenoceptors in indoramin. Br J Clin Pharmacol 17: 719–728Google Scholar
- Rosendorff C (1976) Prazosin: Severe side-effects are dose dependent. Br Med J 2: 508Google Scholar
- Rubin PC, Blaschke TF (1980) Studies on the clinical pharmacology of prazosin. I. Cardiovascular catecholamine and endocrine changes following a single dose. Br J Clin Pharmacol 10: 23–32Google Scholar
- Verbesselt R, Mullie A, Tjandramage TB, Deschepper PJ, Dessan (1976) The effect of food intake on the plasma kinetics and toleration of prazosin. Acta Ther 2: 27–39Google Scholar
- Yamaguchi N, Dechamplain J, Nadeau RA (1977) Regulation of norepinephrine release from cardiac sympathetic fibres in the dog by pre-synaptic and β-receptors. Circ Res 41: 108–110Google Scholar