Conclusions

DONALD G. VIDT, MD

G uanfacine emerges as an impressive new a2-adren- oceptor agonist. The findings reported herein under- score the clinical relevance of my earlier question: Have the central (Y agonists been overlooked in the treatment of hypertension?

The data presented have shown guanfacine to be effective as monotherapy or in combination with diur- etics or other agents. Guanfacine can be given effec- tively once a day, which is certainly advantageous in promoting compliance in the hypertensive patient. Its adverse effects of sedation and dry mouth cannot be ignored. In earlier representatives of this class, these effects contributed to the decreased use of these drugs to control elevated blood pressure (BP]. Nonetheless, the evidence suggests that 1 mg of guanfacine is associ- ated with a relatively low incidence of side effects. A comparatively small number of patients receiving this dosage found it necessary to discontinue therapy be- cause of adverse effects. Higher doses do not appear to be more effective therapeutically. Obviously, the ad- verse-effect profile increases with increments in dos- age. The agent has a favorable metabolic profile and has been associated with no serious long-term toxicity.

Dr. Jerie asked, “Do we need a new antihyperten- sive agent?” I think the answer is yes, because certain- ly the ideal antihypertensive agent has so far eluded us. I think that as long as we can develop new, effec- tive agents that are acceptable to patients, carry re- duced risk and can be administered in a way that would achieve optimal BP results with minimal ad- verse effects, then these drugs represent an appropri- ate addition to our antihypertensive armamentarium.

To summarize the findings from these reports brief- ly, Dr. Reid outlined the clinical advantages of the (Ye agonists in hypertension. They are indeed effective in mild and moderate hypertension and are well tolerat- ed in low doses. With the possible exception of (Y meth- yldopa, long-term toxicity is not a problem. Unlike other classes of antihypertensives, the az-adrenocep- tor agonists do not cause increases in other cardiovas- cular risk factors. Centrally mediated side effects have been a problem with these agents. Clonidine demon- strates a narrow therapeutic range in the plasma of 0.5 to 1.5 rig/ml. This range produces not only the maxi- mum therapeutic effect, but also the maximum seda-

From the Department of Hypertension and Nephrology, Cleve- land Clinic Foundation, Cleveland, Ohio.

tive effect. Although such data are available only for clonidine at this time, it is appropriate to assume that similar observations will be seen with other drugs in its class. The withdrawal or discontinuation symptoms that often complicate the cessation of clonidine thera- py are less common with guanfacine.

Dr. Scholtysik reviewed studies that support a cen- tral site of guanfacine action, specifically at the (~2 adrenoceptors; he also provided evidence suggesting that guanfacine demonstrates much greater selectivity on central a2 receptors compared with clonidine. There is the possibility that this higher selectivity of guanfacine may allow selective (~2 stimulation at lower total drug doses.

Dr. Kiechel’s work suggests that the pharmacoki- netics of guanfacine are not significantly different in patients with renal dysfunction and that dosage adjust- ments in such patients might not be necessary.

Dr. Rosenthal has demonstrated that the BP reduc- tions in hypertensive patients after 12 weeks of guan- facine administration are associated not only with a significant reduction in peripheral vascular resistance, but also with a reduction in right atria1 pressure or preload. Thus guanfacine may prove useful in the treatment of hypertensive patients with associated congestive heart failure.

Dr. Hauger-Klevene’s provocative findings show that long-term treatment with guanfacine is associated with an actual decrease in serum cholesterol and tri- glyceride values as well as plasma renin activity. Low- er prolactin levels were also measured and glucose metabolism was not affected. This suggestion-that guanfacine might mediate a reduction in the total car- diovascular risk profile-awaits further study with long-term clinical investigations.

Results from Dr. Materson’s multiinvestigator ap- praisal suggest that a l-mg guanfacine dose, in combi- nation with a diuretic, reduces BP with few side ef- fects. Higher doses of 2- or 3-mg guanfacine are no more effective therapeutically but are associated with an increase in adverse effects. Administration of 1-mg guanfacine at bedtime with a diuretic appears to be effective in a high number of patients with mild to moderate hypertension. The dosage was not associat- ed with postural hypotension and terminations from the investigation were extremely low. Preliminary data suggest that a reversal of left ventricular hypertro- phy may accompany long-term guanfacine treatment.

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March 28,1986 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 57 61E

Again, clinical assessments of this effect should be initiated.

Dr. Keenan has confirmed the 24-hour duration of guanfacine action in combination with a diuretic. There was no difference in BP measurement whether it was checked 12 or 24 hours after the last dose. This is in agreement with other findings.

Dr. Wilson has shown that guanfacine has less of a tendency to produce withdrawal symptoms and that it produces less morning drowsiness. At the daily dos- ages used in this study-l to 3 mg of guanfacine versus 0.2 to 0.6 mg of clonidine-there was little tendency to overshoot BP, and no significant increases in urinary catecholamines were seen.

Dr. Fillingim’s findings demonstrate that mono- therapy with guanfacine, 1 mg at bedtime, had no effect 4 weeks after initiation of therapy on plasma volume, total blood volume or aldosterone concen- trations, but was associated with a modest, statisti- cally significant reduction in BP. Guanfacine had no ef- fects on cholesterol, triglycerides or low density or high density lipoprotein concentrations, although these findings are from a much shorter term study.

Dr. Jerie reviewed some of his extensive studies to show the efficacy and safety of guanfacine over a wide range of dosages, from 0.5 to as high as 25 mg/day in a large group of hypertensive patients, many of whom had significant cardiovascular and renal complica-

tions in addition to mild to moderate hypertension. Guanfacine has been shown to be effective in patients with congestive heart failure, diabetes, renal paren- chymal disease and associated renal dysfunction. It has been effective alone or in combination with other agents in patients with moderate to severe hyperten- sion. Regardless of the specific dosage, once- and twice-a-day administration appears to achieve control in a higher percentage of patients than that associated with 3-times-a-day administration. The once-a-day dosage also appears to be associated with fewer side effects. There was no evidence of long-term toxicity in these patients.

In summary, the data presented show guanfacine to be effective and safe in the treatment of patients with mild to moderate hypertension. Long-term administra- tion is well tolerated, particularly in low dosage, and adverse metabolic effects seen with some other classes of agents have not been observed. In particular, glu- cose metabolism is not adversely affected while serum cholesterol and triglyceride values are moderately de- creased. The use of a low daily dose of 1 mg of guanfa- tine, with its longer duration of action, appears to re- duce adverse side effects and increase patient adherence. This observation, if applicable to other central (Y~ agonists, may serve to further increase the applicability of this class of agents in the management of arterial hypertension.