BRETYLIUM
   &

GUANETHIDINE

Tbo New Drugs Producing Spec;fic Blockade
of the Symprrthetic Nervous System

      EDWARD D. FREIS, M.D.
Senior Medical Investigator, Veterans Administra-
tion Hospital, Washington, DC.

The purpose of this communication is to acquaint
practicing physicians with a new class of antihyper-
tensive agents. The ganglion blocking drugs are rec-
ognized as the most potent and reliable antihyperten-
sive agents presently available. In clinical practice,
however, their use is attended by a high incidence of
side effects. Ganglioplegic drugs inhibit transmission
through all autonomic ganglia, parasympathetic as
well as sympathetic. Such side effects of parasym-
pathetic blockade as paralysis of visual accommodation,
dryness of the mouth, and constipation have contrib-
uted to the discomforts patients frequently experience
with these agents. Since, as far as is known, the anti-
hypertensive effects of these drugs result entirely from
blockade of the sympathetic and not at all from block-
ade of the parasympathetic system, new agents have
been sought which would block transmission only
through sympathetic nerves.

As often happens, two such drugs have been dis-
covered practically simultaneously, one in England,
the other in this country. The British compound is
bretylium tosylate (Darenthin@) The American drug
is guanethidine (Ismelin@) . Both agents seem to block
transmission at or near the sympathetic nerve endings.
They do not block at the ganglia and they apparently
have no inhibiting effect on parasympathetic transmis-
sion. Unlike the adrenergic blocking agents such as
tolazoline and phentolamine, they do not neutralize or
reverse the pressor effects of circulating epinephrine
and norepinephrine. They represent, in truth, a new

class of compounds whose blocking effects seem to be
limited to transmission of sympathetic nerve impulses.
guanethidine

The pharmacology of guanethidine was described in
1959. Maxwell and associates found that the drug
lowered blood pressure in hypertensive animals,
blocked transmission through postganglionic sympa-
thetic but not parasympathetic nerves, and did not
prevent the pressor effects of injected norepinephrine.
In addition, they reported an unusually long dura-
tion of action. The effects of a large, single dose were
found to last for one week or longer.

Clinical trials in several clinics quickly confirmed
the fact that guanethidine was a potent antihyperten-
sive agent in doses of 25 to 200 mg. per day, depending
on the responsiveness of the patient. Postural hypo-
tension resulted, although blood pressure was reduced
to a lesser degree in the supine position as well, similar
to effects of the ganglion blocking drugs; however,
unlike the latter, side effects of constipation, loss of
visual accommodation, dry mouth, and difficulty in
emptying the urinary bladder were entirely absent.
Indeed, diarrhea, which may be caused by unopposed
parasympathetic activity, has been a common side
effect. Bradycardia has been another evidence of para-
sympathetic predominance. Libido and erection are not
affected although ejaculation which is a sympathetic
function may not be consummated.

The long duration of action of guanethidine has
necessitated certain precautions in adjusting dosages.
Since the duration of action spans a period of approxi-
mately one week the daily dosages given during that
period will, to a certain extent, be cumulative. There-
fore, in ambulatory patients it has been found to be

Chemical Structure of Guanethidine and Bretylium Tosylate
r         1

i 0 - CHz-CU2-NHC /,N"
              `NH2    HZ%

                   2
[2-(octahydro-1-azocinyl)-ethyl1 guanidine sulfate, guanethidine.
            CH3

/ \
0     I
  - CHz - N+- C2Hs
- BR.    I

            CM3
N-0-bromobenzyl-N-ethyl-NN-dimethylammonium ion, bretylium.


prudent to wait at least one week before elevating the
dose level. When dosages were raised more rapidly
orthostatic hypotension and collapse could be precipi-
tated, and sometimes they lasted for four or five days
after the drug was withdrawn. This, of course, is a
more important problem in ambulatory than in hos-
pitalized patients. In the former, dosage increases
should be planned so as gradually to approach a thera-
peutic maintenance level, at which daily destruction
and excretion equal the daily intake.

Action Sites: Ganglion Blocking Agents, Guanethidine & Bretylium

                Pregonglionic fiber    z;;nethidlne
                                Bretylium

bretylium tosylate

blocking drugs

At about the same time that findings with guanethi-
dine were announced a group of British investigators
published their report that bretylium tosylate, a com-
pound which is chemically wholly different from
guanethidine, also produced selective block of the
sympathetic nervous system. Administration of the
isotopically labeled compound showed that it was in-
corporated into sympathetic nerves in higher concen-
tration than in other nervous tissue.

Ganglion blocking agents inhibit transmission through autonomic
ganglia (sympathetic  and parasympathetic), guanethidine and
bretylium at or near endings of postganglionic sympathetic fibers.

Clinical trials of bretylium first in England and then
in this country indicated that the drug produced pre-
dominantly a postural hypotension and that it was
free of the side effects of parasympathetic blockade.
It was poorly absorbed from the gastrointestinal tract
so that large doses, sometimes exceeding 300 mg. per
day, were required. Unlike guanethidine, the duration
of action of the drug was approximately eight to twelve
hours, so that dosages could be administered every
eight hours and elevated fairly rapidly to the effective
level without danger of precipitating a prolonged hypo-
tensive episode. Also, unlike guanethidine, the side
effects of parasympathetic predominance-diarrhea
and bradycardia-did not occur.

drug. The only advantage of guanethidine and brety-
lium is the absence of parasympathetic blocking effects.
Because of the effect of blocking agents of either type
on orthostatic blood pressure meticulous dosage adjust-
ment is required in order to avoid postural collapse.
With ambulatory patients, in my experience, the best
guide is frequent home blood pressure recordings
taken when the patient is standing in the erect posi-
tion. Unfortunately, guanethidine and bretylium do
not do away with the necessity for such precautions.
Just as chlorothiazide and other saluretic agents have
enhanced the effectiveness of the ganglion blocking
drugs so have they also been used to advantage with
bretylium and guanethidine.

Among the principal shortcomings of bretylium are:
(1) an unusually wide range of dose responses (from
300 to over 3000 mg. per day in divided dosage) in
different patients; (2) lack of antihypertensive poten-
cy in more severe and resistant cases; and (3) develop-
ment of tolerance in some patients. A side effect pe-
culiar to this drug has been the development of bi-
lateral pain and tenderness but without swelling, heat,
or redness in the region of the parotid gland. The
cause is unknown and it most often occurs when dos-
ages are elevated to levels of two or more grams per day.
general comments

It is still too early to say how important a place
these agents will have in the clinical management of
patients with hypertension or to be detailed and spe-
cific about the most effective means for administering
these drugs. Probably they represent promising fore-
runners of better agents to come which will combine
the potency of the ganglion blocking drugs without
their parasympathetic blocking effects.
references

The antihypertensive effect of both of these agents
is primarily orthostatic. In this respect they are similar
to the ganglion blocking agents in that the blood pres-
sure in the supine position is the least affected by the

BOURA, A. L. A., et al.: Darenthin: Hypotensive Agent of a New
Type, Lancet 2:17 (July 11) 1959.
DOLLERY, C. T., et al.: Bretylium Tosylate in the Treatment of
Hypertension, Lancet I:296 (Feb. 6) 1960.
FROHLICH, E. D., and FREIS? E. D.: Clinical Trial of Guane-
thidine, a New Type of Antrhypertensive Agent, M. Ann. Dis-
trict of Columbia 28:419 (Aug.) 1959.
MAXWELL, R. A., et al.: Pharmacology of CZ(octahydro-l-
azocinyl) -ethyl 1 -guanidine sulfate (X-5864), J. Pharmacol. &
Exper. Therap. 128:22 (Jan.) 1960.
PAGE, I. H., and DUSTAN, H. P.: A New Potent Antihypertensive
Drug. Preliminary Study of 12.(octahydro-l-azocinyl)-ethyll-
guanidine Sulfate (Guanethidine), J. Am. M. A. 170: 1265
(Julv II) 1959.
I~C~ARDS~N, D. W. and WYSO,, E. M.: Effective Reduction in
Blood Pressure without Gangliomc Blockade, Virginia M. Month.
86:377 (July) 1959.

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