, Volume 26, Issue 3, pp 212–229 | Cite as


A Review of its Pharmacodynamic Properties and Therapeutic Efficacy in Hypertension
  • Barbara Holmes
  • R. N. Brogden
  • R. C. Heel
  • T. M. Speight
  • G. S. Avery
Drug Evaluations


Synopsis: Guanabenz1 is an orally active central α2-adrenoceptor agonist. Its antihypertensive action is thought to result from a decrease in sympathetic outflow from the brain to the peripheral circulatory system as a result of stimulation of central α2-adrenoceptors. In mild to moderate hypertension it is as effective as methyldopa and clonidine in lowering blood pressure when used as the sole treatment. As with these drugs, guanabenz may be combined with a diuretic to increase its blood pressure-lowering effect. The overall incidence of side effects seen with guanabenz was at least as high as with methyldopa or clonidine, and side effects such as drowsiness or dry mouth have been bothersome enough to lead to discontinuation of guanabenz therapy in some patients. However, particularly troublesome effects such as sodium retention, depression or sexual dysfunction which may occur with methyldopa or clonidine have not been reported with guanabenz.

Pharmacodynamic Properties: Guanabenz causes a decrease in blood pressure both in supine and standing positions without alterations of normal postural mechanisms. Animal studies have shown that intravenous guanabenz penetrates the central nervous system, and reduces blood pressure, heart rate, and spontaneous sympathetic discharge by an interaction with post-synaptic α-adrenoceptors, primarily at the bulbar level. Additionally, however, although not a classic adrenergic neuron-blocking drug, guanabenz does decrease the response to peripheral sympathetic nerve stimulation in animal preparations. This fact may explain the observation that in long term therapy its antihypertensive effect appears to be due to a decrease in peripheral resistance. In hypertensive patients, guanabenz brings about a decrease in heart rate, but no significant change in left ventricular stroke volume, cardiac output or ejection fraction. Effective control of blood pressure in patients was not associated with any changes in glomerular filtration rate, sodium balance, plasma renin activity, mean maximal urine osmolality, fluid intake, urine volume or serum sodium concentration. In several studies, patients on medium to long term therapy have experienced a decrease in bodyweight, but the mechanism of this weight loss has not been established. Small decreases in serum cholesterol levels have been recorded in patients on long term therapy.

Pharmacokinetics: Maximum concentrations of guanabenz in plasma (1.2 to 5.2 ng/ ml) were reached 2 to 5 hours after administration of capsules containing 16 or 32mg of 14C-labelled guanabenz. Unchanged drug accounted for less than 3% of the peak 14C concentration in plasma, indicating that most of the radioactivity was due to metabolites. The effect of food on absorption has not been studied. The drug is extensively metabolised and large amounts of metabolites are recovered in the urine in the first 24 hours. Guanabenz is 90% bound to human plasma proteins. Less than 1% of the dose is excreted as unchanged drug, the greatest proportion being in the form of the inactive metabolite (E)-p-hydroxyguanabenz. The site or sites of metabolism and the consequences of renal or hepatic insufficiency on the kinetics of guanabenz have yet to be determined.

Therapeutic Trials: Guanabenz has undergone trials both as the sole agent for initial antihypertensive therapy and in combination with a thiazide diuretic in previously treated patients with mild to moderate hypertension. In nearly all the studies the dosage has been titrated for each patient within the range of 8 to 64mg daily, the majority of patients being controlled on up to 32 mg/day. Non-comparative trials have suggested that guanabenz is an effective antihypertensive agent in about 70% of patients, this being confirmed in double-blind placebo-controlled trials. The drug has been consistently better than placebo in parallel group and crossover studies. Guanabenz (16 to 64mg) produced a similar response rate, but not quite as large a mean decrease in blood pressure as methyldopa (500 to 2000mg) in the few studies reported so far. Trials comparing guanabenz (8 to 64mg) and clonidine (0.2 to 0.9mg) suggest that they are almost equally effective, with similar decreases in blood pressure and response rates. In preliminary studies, guanabenz (4 to 64mg) has been found similar in efficacy to hydrochlorothiazide (25–100mg) in patients with mild to moderate hypertension. Treatment with guanabenz plus hydrochlorothiazide is more effective than that with either drug alone. However, side effects tend to be more frequent with the combination. In the only study comparing guanabenz with a β-adrenoceptor blocking drug, the antihypertensive effects of guanabenz (16mg) were similar to those of propranolol (120mg).

Side Effects: The most frequent side effects associated with guanabenz therapy are drowsiness, dry mouth, dizziness and weakness, and such effects may lead to discontinuation of therapy in some patients. Apart from a decrease in heart rate, cardiovascular effects have seldom occurred. Gastrointestinal symptoms and impotence have been rare. Postural hypotension has not proved to be a problem. No significant abnormalities of renal or liver function tests have been reported. A withdrawal syndrome compatible with sympathetic overactivity has been described, and this finding needs further investigation but no reports of rebound hypertension have been documented. In comparative studies, the overall incidence of side effects with guanabenz was at least as high as with drugs such as methyldopa or clonidine, although some of the particularly troublesome effects that may occur with these drugs (sodium retention, depression, sexual dysfunction) have not been reported at this stage of the drug’s development.

Dosage and Administration: Therapy should begin with 4mg twice a day whether guanabenz is prescribed alone or in combination with a thiazide diuretic. Increases can be made in increments of 4 to 8mg daily at 1- to 2-week intervals, depending on the patient’s response, up to a maximum of 64mg daily.


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  1. Ananias Figueira da Silva, J.; Privato de Oliveira Capaceia, J. and Cohen, I.: Assessment of a new antihypertensive agent, 2,6-dichlorobenzylidene amino guanidine acetate (guanabenz): A double-blind, crossover trial against placebo. Pharmatherapeutica 1: 1–7 (1976).Google Scholar
  2. Bauer, J.H. and Burch, R.N.: Comparative Studies: Guanabenz versus propranolol as first-step therapy for the treatment of primary hypertension. Cardiovascular Reviews and Reports 4: 9–17 (1983).Google Scholar
  3. Baum, T. and Shropshire, A.T.: Inhibition of spontaneous sympathetic nerve activity by the antihypertensive agent Wy 8678. Neuropharmacology 9: 503–506 (1970).PubMedCrossRefGoogle Scholar
  4. Baum, T. and Shropshire, A.T.: Studies on the centrally mediated hypotensive activity of guanabenz. European Journal of Pharmacology 37: 31–44 (1976a).PubMedCrossRefGoogle Scholar
  5. Baum, T. and Shropshire, A.T.: Aspects of the antihypertensive action of indoramin and guanabenz; in Scriabine and Sweet (Eds) New Antihypertensive Drugs, pp. 369–386 (Spectrum Publications, New York 1976b).Google Scholar
  6. Baum, T.; Shropshire, A.T.; Rowles, G.; Van Pelt, R.; Fernandez, S.P.; Eckfeld, D.K. and Gluckman, M.I.: General pharmacologic actions of the antihypertensive agent 2,6-dichlorobenzylidene aminoguanidine acetate (Wy 8678). J. Pharmacol. Exp. Therap. 171: 276–287 (1970).Google Scholar
  7. Bolme, P.; Corrodi, H. and Fuxe, K.: Possible mechanism of the hypotensive action of 2,6-dichlorobenzylidine aminoguanidine: Evidence for central noradrenaline stimulation. European Journal of Pharmacology 23: 175–182 (1973).PubMedCrossRefGoogle Scholar
  8. Bosanac, P.; Dubb, J.; Walker, B.R.; Goldberg, M. and Agus, Z.S.: Renal effects of guanabenz: A new antihypertensive. Journal of Clinical Pharmacology 16: 631–636 (1976).PubMedGoogle Scholar
  9. Braden, G.; Walker, B.R. and Cox, M.: Effects of guanabenz on sodium and water homeostasis. Clinical Pharmacology and Therapeutics 31: 206 (1982).Google Scholar
  10. Deitch, M.W.; Littman, G. and Walker, B.R.: Comparison of guanabenz and propranolol in hypertension. (Submitted for presentation — American Society for Clinical Pharmacology and Therapeutics, March 1983a).Google Scholar
  11. Deitch, M.W. and Engelman, K.: Guanabenz compared to hydrochlorothiazide as initial therapy in hypertension. (In press, Wyeth 1983).Google Scholar
  12. DeRidder, J.H. and Merchandise, P.: Preliminary clinical trial with a new hypotensive guanabenz, in a group of hypertensive patients. Acta Cardiologica 35: 349–355 (1980).Google Scholar
  13. Dixon, G.T. and Johnson, E.S.: Efficacy of antihypertensive drugs. Lancet 1: 515–518 (1976).PubMedCrossRefGoogle Scholar
  14. Dziedzic, S.W.; Elijovich, F.; Felton, K.; Yaegar, D. and Krakoff, L.R.: Effect of guanabenz on blood pressure responses to posture and exercise. Clin. Pharmacol. Ther. 83: 151–154 (1983).CrossRefGoogle Scholar
  15. Ruck, E.R.; Homon, C.A.; Knowles, J.A. and Ruelius, H.W.: Differential binding of guanabenz and its metabolites to cerebral α2-receptors: The basis for a radiological assay specific for the drug. Drug Development Research 3: 91–99 (1983).CrossRefGoogle Scholar
  16. Fuller, R.W.; Snoddy, H.D. and Marshall, W.S.: Lowering of rat brain 3-methoxy-4-hydroxyphenylethylene glycol sulphate (MOPEG sulphate) concentration by 2, 6-dichlorobenzylidene aminoguanidine. Journal of Pharmacy and Pharmacology 29: 375–376 (1977).PubMedCrossRefGoogle Scholar
  17. Golub, M.S.; Eggena, P.; Barrett, J.D.; Thananopavarn, C. and Sambhi, M.P.: Fluid volumes during antihypertensive therapy with guanabenz in mild hypertension. Clinical Pharmacology and Therapeutics 2: 230 (1982).Google Scholar
  18. Grabie, M.; Nussbaum, P.; Goldfarb, S.; Walker, B.R.; Goldberg, M. and Agus, Z.: Effects of methyldopa on renal haemodynamics and tubular function. Clinical Pharmacology and Therapeutics 27: 522–527 (1980).PubMedCrossRefGoogle Scholar
  19. Grenfell, R.F.: Double-blind study of guanabenz acetate in hypertensive patients. Southern Medical Journal 76: 199–201 (1983).PubMedCrossRefGoogle Scholar
  20. Hirvonen, P.; Pörsti, P. and Frick, M.H.: A comparison of guanabenz and methyldopa in hypertension. Current Therapeutic Research 27: 197–204 (1980).Google Scholar
  21. Holland, O.B.; Fairchild, C. and Gomez-Sanchez, C.E.: Effect of guanabenz and hydrochlorothiazide on blood pressure and plasma renin activity. J. Clin. Pharmacol. 21: 133–139 (1981).PubMedGoogle Scholar
  22. Jarrot, B.; Louis, W.J. and Summers, R.L.: The effect of a series of clonidine analogues on [3H] clonidine binding in rat cerebral cortex. Biochemical Pharmacology 28: 141–144 (1979).CrossRefGoogle Scholar
  23. Kluyskens, Y. and Snoeck, J.: Comparison of guanabenz and clonidine in hypertensive patients. Current Medical Research and Opinion 6: 638–643 (1980).PubMedCrossRefGoogle Scholar
  24. Leary, W.P.; Asmal, A.C. and Williams, P.C.: Evaluation of the efficacy and safety of guanabenz versus clonidine. South African Medical Journal 55: 83–85 (1979).PubMedGoogle Scholar
  25. Marmo, E.; Saini, R.K.; Caputi, A.P. and Vacca, C.: Cardiovascular profile of BR-750 (2,6,dichloro-benzylidine-aminoguanidine acetate). Research communications in Chemical Pathology and Pharmacology 6: 391–406 (1973).PubMedGoogle Scholar
  26. Meacham, R.H.; Chiang, S.T.; Kick, C.J.; Sisenwine, S.F.; Jusko, W.J. and Ruelius, H.W.: Pharmacokinetic disposition of guanabenz in the rhesus monkey. Drug Metabolism and Disposition 9: 509–514(1981).PubMedGoogle Scholar
  27. Meacham, R.H.; Emmett, M.; Kyriakopoulos, A.A.; Chiang, S.T.; Ruelius, H.W.; Walker, B.R.; Narins, R.G. and Goldberg, M.: Disposition of l4C-guanabenz in patients with essential hypertension. Clin. Pharmacol. Ther. 27: 44–52 (1980).PubMedCrossRefGoogle Scholar
  28. McMahon, F.G.; Cole, P.A.; Boyles, P.W. and Vanov, S.K.: Study of a new antihypertensive (guanabenz). Current Therapeutic Research 16: 389–397(1974).PubMedGoogle Scholar
  29. McMahon, F.G.; Ryan, J.R.; Jain, A.K.; Vargas, R. and Vanov, S.K.: Guanabenz in essential hypertension. Clinical Pharmacology and Therapeutics 21: 272–277 (1977).PubMedGoogle Scholar
  30. Misu, Y.; Fujie, K. and Kubo, T.: Presynaptic dual inhibitory actions of guanabenz on adrenergic transmission. European Journal of Pharmacology 77: 177–181 (1982).PubMedCrossRefGoogle Scholar
  31. Misu, Y. and Kubo, T.: Central and peripheral cardiovascular responses of rats to guanabenz and clonidine. Japanese Journal of Pharmacology 32: 925–928 (1982).PubMedCrossRefGoogle Scholar
  32. Nash, D.: Clinical trial with guanabenz, a new antihypertensive agent. Journal of Clinical Pharmacology 13: 416–421 (1973).PubMedGoogle Scholar
  33. Ram, V.C.S.; Holland, B.; Fairchild, C. and Gomez-Sanchez, C.E.: Withdrawal syndrome following cessation of guanabenz therapy. Journal of Clinical Pharmacology 19: 148–150 (1979).PubMedGoogle Scholar
  34. Roller, L.: Sympathomimetic and adrenergic neuron blocking actions of compounds in an isolated arterial preparation. Australian Journal of Pharmaceutical Sciences 5: 35–40 (1976).Google Scholar
  35. Saini, R.K.; Caputi, A.P. and Marmo, E.: Cardiovascular profile of BR 750 (2,6-dichlorobenzylidene aminoguanidine acetate). Farmaco Edizione Pratica 28: 359 (1973).PubMedGoogle Scholar
  36. Santoro, R.; Sensale, P. and Acierno, D.: Clinical trial with a new antihypertensive drug: Guanabenz. Riforma Medica 93: 955–960 (1978).Google Scholar
  37. Shah, R.S.; Walker, B.R.; Vanov, S.K. and Helfant, R.H.: Guanabenz effects on blood pressure and non-invasive parameters of cardiac performance in patients with hypertension. Clinical Pharmacology and Therapeutics 19: 732–737 (1976).PubMedGoogle Scholar
  38. Vanov, S. and Vergis, J.: Guanabenz in essential hypertension. Clinical Pharmacology and Therapeutics 17: 245–246 (1975).Google Scholar
  39. Vanov, S.; Singer, A. and Walker, B.R.: A multicentre trial of guanabenz. Clinical Research 24: 259 (1976).Google Scholar
  40. Walker, B.R.; Deitch, M.W.; Schneider, B.E. and Gold, J.A.: Multicentre comparison of guanabenz and hydrochlorothiazide in hypertension (submitted for publication — American Society of Nephrology, Washington D.C., November 1980c).Google Scholar
  41. Walker, B.R.; Deitch, M.W.; Schneider, B.E.; Hare, L.E. and Gold, J.A.: Long-term therapy of hypertension with guanabenz. Clinical Therapeutics 4: 217–228 (1981a).PubMedGoogle Scholar
  42. Walker, B.R.; Deitch, M.W.; Schneider, B.E. and Hare, L.E.: Comparative antihypertensive effects of guanabenz and methyldopa. Clinical Therapeutics 4: 275–284 (1981b).PubMedGoogle Scholar
  43. Walker, B.R.; Deitch, M.W.; Gold, J.A. and Levey, B.A.: Evaluation of guanabenz added to hydrochlorothiazide therapy in hypertension. J. Int. Med. Res. 10: 131–139 (1982a).PubMedGoogle Scholar
  44. Walker, B.R.; Hare, L.E. and Deitch, M.W.: Comparative antihypertensive effects of guanabenz and clonidine. Journal of International Medical Research 10: 6–14 (1982c).PubMedGoogle Scholar
  45. Walker, B.R.; Hare, L.E.; Deitch, M.W. and Gold, J.A.: Comparative effects of guanabenz alone and in combination with hydrochlorothiazide as initial antihypertensive therapy. Current Therapeutic Research 31: 764–775 (1982b).Google Scholar
  46. Walker, B.R.; Schneider, B.E. and Gold, J.A.: A two-year evaluation of guanabenz in the treatment of hypertension. Current Therapeutic Research 27: 784–796 (1980a).Google Scholar
  47. Walker, B.R.; Schneider, B.E.; Rudnick, M.R. and Gold, J.A.: Effects of placebo versus guanabenz on hypertensive outpatients. J. Int. Med. Res. 8: 303–313 (1980b).PubMedGoogle Scholar
  48. Walker, B.R.: Shah, R.S.; Ramanathan, B.K.; Vanov, S.K. and Helfant, R.H.: Guanabenz and methyldopa on hypertension and cardiac performance. Clinical Pharmacology and Therapeutics 22: 868–874 (1977).PubMedGoogle Scholar
  49. Walson, P.D.; Rath, A.; Allen, H.D. and Deitch, M.D.: Guanabenz for paediatric hypertension. Clinical Pharmacology and Therapeutics 27: 292 (1980).Google Scholar

Copyright information

© ADIS Press Australasia Pty Ltd 1983

Authors and Affiliations

  • Barbara Holmes
    • 1
  • R. N. Brogden
    • 1
  • R. C. Heel
    • 1
  • T. M. Speight
    • 1
  • G. S. Avery
    • 1
  1. 1.ADIS Drug Information ServicesBirkenhead, Auckland 10New Zealand

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