Antihypertensive and Hemodynamic Properties
of the New Beta Adrenergic
Blocking Agent Timolol

By JosepH A. Franciosa, M.D., Epwarp D. Frets, M.D.,

AND JAMES Conway, M.D.

SUMMARY

The antihypertensive activity of timolol, a new beta adrenergic blocking agent, was assessed
in hypertensive patients. In hospitalized patients timolol, 5 mg orally every 8 hr for one week,
resulted in a significant although mild reduction of blcod pressure with diastolic pressure fall-
ing from a mean of 101 mm Hg to 91 mm Hg. Heart rate and cardiac output fell while total
peripheral resistance increased. The Valsalva response, the reflex tachycardia following in-
halation of amyl nitrite and the cardiovascular responses to infusion of isoproterenol were sig-
nificantly inhibited. Timolol also was compared to propranolol in a randomized double-blind
outpatient trial. The antihypertensive and bradycrotic effects of the two drugs were similar. Heart
rate was reduced 18% by both drugs (P <0.05). Supine diastolic pressure fell 9% (P< 0.05).
Unlike the short term effects of timolol, and in contrast to propranolol, cardiac output did not
remain reduced after five weeks of continuous treatment with timolol. It is concluded that timolol

merits further investigation as an antihypertensive agent.

Additional Indexing Words:
Hypertension Propranolol

IMOLOL [( — )-3-morpholino-4-(3-tertbutyl-

amino-2-hydroxypropoxy )-1,2,5-thiadiazole hy-
drogen maleate] is a new beta adrenergic
blocking agent which within one hour of a 5 mg
oral dose reduces heart rate and cardiac output by
20%. It also diminishes the sympathetic reflex
responses to the Valsalva maneuver and amyl nitrite
inhalation. Like propranolol it does not reduce
arterial pressure acutely and does not possess
intrinsic sympathomimetic activity.

Beta blocking agents can effectively lower blood
pressure in properly selected patients without
orthostatic hypotension or other important side
effects.2* The present study was designed to assess
the antihypertensive properties of timolol and to

 

From the Veterans Administration Hospital and the
Department of Medicine, Georgetown University, Washing-
ton, D. C.

Supported in part by a research grant from Merck Sharp
& Dohme, West Point, Pennsylvania.

Address for reprints: Dr. Edward D. Freis, Senior Medical
Investigator, VA Hospital, 50 Irving Street, N.W., Washing-
ton, D. C. 20422.

Received December 21,
publication February 16, 1973.

1972;

revision accepted for

Sympathetic blockade

118

Amy] nitrite

observe its hemodynamic effects following con-
tinued administration of the drug.

Methods

The study was performed in two parts, the first
consisting of hemodynamic observations in hospitalized
patients with mild essential hypertension, the second
being a comparison of timolol and propranolol in
hypertensive outpatients.

Part I

Six male volunteers ranging from 46 to 56 years of
age with previously untreated mild essential hyperten-
sion (diastolic blood pressure 90 to 110 mm Hg) were
selected for study. All patients had initial laboratory
studies including hemogram, urinalysis, fasting blood
sugar, serum electrolytes, blood urea nitrogen, serum
creatinine, chest X-ray, electrocardiogram, urinary
catecholamines, and intravenous pyelogram. Patients
with any of the following were excluded: history of
severe heart failure or myocardial infarction, resting
heart rate below 50 beats per minute, insulin-requiring
diabetes mellitus, hepatic disease, bronchial asthma or
emphysema or renal failure defined as a serum
creatinine level of 2 mg @% or higher or abnormal
function on intravenous pyelogram. All subjects were
hospitalized at least three days prior to study during
which time blood pressures were recorded three times
daily. Blood pressures were recorded following 10 min
in the supine position and 3 min after standing erect. A

Circulation, Volume XLVIH, July 1973
PROPERTIES OF TIMOLOL

diastolic blood pressure averaging 90 mm Hg or above
in the supine position during this period was used as
the criterion for entrance into the study.

Hemodynamic measurements were carried out follow-
ing the three to six day pretreatment control period. A
Teflon needle was inserted into the brachial artery and
PE 50 tubing was advanced via an antecubital vein into
the right atrium. Arterial and venous pressures were
recorded using a P23Db Statham pressure transducer
and a Honeywell Visicorder. Cardiac output was
determined by the dye. dilution technique using
indocyanine green. The Valsalva maneuver was per-
formed by having the patient blow forcibly into a
closed tube while maintaining a pressure of 40 mm Hg
for 10-15 sec. Maximal blood pressure overshoot and
heart rate during the period of reflex bradycardia were
measured to quantitate the response. Amyl nitrite
inhalation was carried out by having the patient take
two deep breaths from a vial containing 0.3 ml of the
substance. The maximum fall in diastolic blood pressure
and peak tachycardia were used to quantitate the
response. Isoproterenol was infused intravenously
starting at 1 wg/min and titrating upward until a 25%
increase in heart rate was obtained or to a maximum of
4 wg/ min.

Following these control determinations 5 mg of
timolol was given orally and one hour later the
hemodynamic measurements were repeated. Continu-
ous treatment with timolol was then initiated at 5 mg
every 8 hr and maintained for seven davs. Dosage was
adjusted to maintain a heart rate of 50-70 beats/min in
the supine position. Half of the patients remained on
the initial dose and half were increased to 10 mg every
eight hours. On the final day of treatment the morning
dose was omitted and the patient was brought to the
laboratory where the hemodynamic measurements were
repeated before and one hour after the 5 or 10 mg dose
of timolol.

Part IT

From an outpatient clinic population 28 male
volunteers with a previous diagnosis of essential
hypertension were selected. The same exclusions
described in part I were applied to these patients. All
antihypertensive medications were discontinued at least
three weeks prior to entry into the study; in the case of
Rauwolfia derivatives this was extended to six weeks.
The patients selected were those whose diastolic blood
pressure ranged between 90 and 125 mm Hg during
this period of no treatment. Placebo. two capsules t.i.d.,
was given during the first two weeks of the trial.
Patients were then randomly assigned, double blind, to
either propranolol. 80 mg (2 capsules) t.i.d. or timolol
10 mg (2 capsules) t.id. Treatment with active drug
lasted for five weeks, after which all patients were
again given placebo for two more weeks.

All patients were seen by the same physician at
weekly intervals at which time they were weighed;
heart rate and blood pressure were recorded after 10
min supine and 3 min standing, and signs and
symptoms of heart failure or other complications were
looked for. If the diastolic blood pressure was not
reduced to normal or 10 mm Hg lower than had been

Circulation, Volume XLVI, July 1973

119

present the preceding week, the dose of active drug
was increased by one capsule t.i.d. to a maximum of
double the starting dose. Dosage was not increased if
the heart rate was below 60 beats per min and was
decreased by one capsule t.i.d. if the heart rate was
below 50 beats per min.

In consenting individuals hemodynamic measure-
ments were made just before and at the end of the five
week active drug treatment period. Cardiac output,
intraarterial and venous pressures were recorded and
amyl nitrite inhalation was performed employing the
same techniques as described in part I. Patients were
instructed to take their usual morning dose of
medication 1-2 hr prior to reporting to the laboratory
and measurements were made under the same general
conditions in both treatment groups.

Results

Part I
Blood Pressure and Heart Rate

Changes in heart rate and blood pressure are
summarized in table 1. Every patient experienced a
fall in blood pressure without orthostatic hypoten-
sion. The average daily supine blood pressures and
heart rates for all patients are shown in figure 1.
Treatment with timolol (5 mg every 8 hr) was
begun on day seven and continued through day 13.
A definite reduction in blood pressure was evident
by the second day of treatment and became more
pronounced with continuation of therapy. In the
posttreatment period blood pressure returned to-
ward pretreatment levels suggesting that the
observed fall in blood pressure was not due to a
placebo effect. The fall in blood pressure seemed to
correspond with the decline in heart rate and
likewise when treatment was stopped blood pres-
sure rose parallel] with the heart rate suggesting that
the change in blood pressure was closely related to

Table 1

Mean Values of Heart Rate and Blood Pressure in Six
Hospitalized Hypertensive Patients Treated with Timolol
for One Week

 

 

 

Control Treated ™% Reduction
Supine
Heart rate (per min) 82 72 12.9
Systolic blood pressure
(mm Hg) 139 129 7.2
Diastolic blood pressure
(mm Hg) 101 91 9.9
Standing
Heart rate (per min) 98 80 18.6
Systolic blood pressure
(mm Hg) 139 129 7.2
Diastolic blood pressure
(mm Hg) 108 100 7A

 
120

BLOOD PRESSURE
(mm Hg)
HEART RATE
(BEATS/MIN.)

sO
140
205
lOO fF

| 9-0-7

80 ‘oe

‘e-- 0-8 4
t

-t— TIMOLOL—>

60 i \ l = I l Il J

cr 3 5 7 9 I 1 1 I?
DAYS

*———- BLOOD PRESSURE
*---*@ HEART RATE

Figure 1]

 

 

 

 

Blood pressure and heart rate responses of six hospitalized
patients during continuous administration of timolol for one
week. Points plotted are mean values for the whole group.

the level of beta blockade. It should be noted that
these patients had predominantly diastolic hyper-
tension, as the mean pretreatment systolic pressure
for the group was only 139 mm Hg.

Hemodynamics

Prior to treatment the mean cardiac output for
the entire group was 5.43 liters/min. This fell by
21% to 4.29 liters/min one hour after the first dose of
timolol (fig. 2). Reduced cardiac output was still
present after one week’s treatment. Since blood
pressure was reduced to a lesser degree than
cardiac output, total peripheral resistance was
increased by timolol. Stroke volume and central
venous pressure were not significantly changed.

Sympathetic Reflex Activity

During the control period inhalation of amyl
nitrite produced a mean fall of 36.3 mm Hg in
diastolic blood pressure while heart rate increased
by a mean of 37.8 beats per min. After the first dose
of timolol diastolic pressure still fell 38.8 mm Hg,
but heart rate rose only 12.5 beats per min. One

FRANCIOSA, FREIS, CONWAY

CARDIAC
OUTPUT
(L/MIN.)

6rnr

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CONTROL INITIAL TD. SINGLE
DOSE FORONE DOSE

 

5mg. WEEK AFTER

P.O. | WEEK'S

; TREATMENT
AFTER TIMOLOL

Figure 2

Effect of timolol on cardiac output in six hospitalized pa-
tients.

week later, blood pressure fell about the same
amount, but the heart rate response was. still
significantly reduced by about 50% (fig. 3).

With respect to the Valsalva maneuver in the
control period the mean increase of blood pressure
during the post-Valsalva overshoot was 22.5 mm Hg
systolic and 23.2 mm Hg diastolic. Heart rate fell
10.5 beats/min. After timolol, the pressure over-
shoot was reduced to 3.8 mm Hg systolic and 7.5
mm Hg diastolic, while heart rate fell only 1.2
beats/min. This response remained unchanged after
one week of treatment.

The effects of isoproterenol infusion on heart rate
and blood pressure were virtually abolished by
timolol. Prior to treatment isoproterenol lowered
diastolic pressure by an average of 12.3 mm Hg and
increased heart rate 29 beats/min. After timolol
there was essentially no response to isoproterenol
infusion (fig. 4). This same response persisted after
one week of therapy.

Since the morning dose of timolol was withheld
prior to the second hemodynamic study, patients

Circulation, Volume XLVUI, July 1973
PROPERTIES OF TIMOLOL

CHANGE IN

HEART RATE
(BEATS/MIN.)

+40 ¢

 

+30 F

 

+207

 

 

+10 F

 

 

 

 

 

 

 

 

 

 

CONTROL INITIAL T.LD. SINGLE
DOSE FOR ONE DOSE

 

5mg. WEEK AFTER
PO. I WEEK'S
, TREATMENT
j
AFTER TIMOLOL
Figure 3

Effect of timolol on amyl nitrite-induced tachycardia in six
hospitalized patients.

were untreated for 12-16 hr. Nevertheless, the beta
adrenergic blocking effects of timolol on the reflex
responses as well as cardiac output and heart rate
were still present before drug administration and
became more pronounced afterward (see column
labelled “tid. for one week” in figs. 2, 3, 4)
suggesting that timolol has a prolonged duration of
action or a cumulative effect.

Part II
Clinical Data

Of a total of 28 patients entering, 24 completed
the outpatient trial. Among the four who were
dropped, one sustained a nonfatal cerebrovascular
accident at the end of the first placebo period, while
two others were dropped because of failure to
adhere to the protocol. Treatment was terminated
in the fourth patient because of an episode of acute
laryngeal edema. However, he was receiving
ampicillin concurrently as treatment for a urinary
tract infection.

Of the 24 patients completing the trial, 13 re-
ceived propranolol and 11 received timolol. The
propranolol-treated patients averaged 48.1 (range
35-60) years of age while the age of those on timolol
averaged 43.6 (range 30-53) years. None of the
patients had greater than Group II hypertensive
retinopathy by the Kieth, Wagener, and Barker

Circulation, Volume XLVI, July 1973

 

 

 

 

 

 

 

 

 

121
CHANGE IN
HEART RATE
(BEATS/MIN)
*30 Fr
+ 24 a
*1I8F
+ l2 L
+6bk
0 LHS Led
-G@ & CONTROL INITIAL TLD. SINGLE
DOSE FOR ONE DOSE
5mg. WEEK AFTER
PO. | WEEK'S
TREATMENT
AFTER TIMOLOL
Figure 4

Effect of timolol on isoproterenol-induced tachycardia on
six hospitalized patients.

criteria. In the propranolol group, 9 of 13 had
Group II changes, and 6 of 11 timolol-treated
patients had similar changes. Electrocardiographic
or radiographic evidence of left ventricular hyper-
trophy was present in five patients taking timolol
and in seven receiving propranolol. Three patients
in the propranolol group had a history of exertional
dyspnea. In one the dyspnea was unchanged during
treatment, one improved, and the other patient
noted transient worsening of symptoms, which was
relieved by decreasing the dosage of medication.
Another patient in this group developed signs and
symptoms of left ventricular failure during the
treatment period but responded quickly to a
reduction of propranolol dosage. No patient receiv-
ing timolol developed symptoms of heart failure or
noted change in preexisting symptoms. No signifi-
cant weight change occurred in either group.

The average total daily dose of drug was 333 mg
for the propranolol group, and 50 mg for the
timolol group.

Blood Pressure and Heart Rate
The changes in heart rate and blood pressure are
summarized in table 2. Control values were
122

Table 2

FRANCIOSA, FREIS, CONWAY

Comparative Effects of Propranolol and Timolol on Mean Values of Heart Rate and Blood Pressure During Out-

patient Trial with 24 Patients

 

 

 

 

Timolol Propranolol
or,
Control Treated redugtion Posttreatment Control Treated Reduction Posttreatment,
Heart rate (per min)
Supine 78 64 17.9 77 75 62 17.3 76
Standing 85 69 18.8 88 85 69 18.8 86
‘Systolic blood pressure (mm Hg)
Supine 169 164 2.8 161 168 155 7.7 167
Standing 168 161 4.8 159 172 149 13.4 158
Diastolic blood pressure (mm Hg)
Supine 112 102 8.9 109 111 101 9.0 109
Standing 117 108 5.4 113 111 104 6.3 113
Amy] nitrite tachycardia
Increase /min +37.8 +15.3 59.5 _— +28.5 +13.5 52.7 —

 

calculated from the average of three readings at
weekly intervals including the preplacebo reading
as well as the two weeks of placebo preceding
administration of active drugs. The averages of
readings during the final two weeks of active drug
treatment, when peak effects were observed, were
used to derive the mean values of the active
treatment period.

Blood pressure fell promptly and was already
significant (P<0.01) after the first week of
treatment in both groups. In the propranolol
treated group diastolic pressure fell from 111 mm
Hg to 105 mm Hg after the first week of treatment,
and eventually dropped to 101 mm Hg at the end of
five weeks of treatment. For timolol treated
patients, diastolic blood pressure was reduced from
112 to 108 mm Hg after one week and fell further
to 102 mm Hg after five weeks. The degree of
diastolic pressure reduction was not significantly
different between the two groups, but systolic
pressure was significantly lowered only in the
propranolol-treated group. Both diastolic blood
pressure and heart rate returned to, or was very
near to pretreatment values in each group during
the final two weeks of placebo administration, but
systolic pressure tended to remain below control
levels, especially in timolol-treated patients.

The changes in heart rate and the degree of
inhibition of amyl] nitrite induced tachycardia were
virtually identical in the two groups suggesting that
the degree of beta blockade achieved was the same
with either drug (table 2).

Other Hemodynamic Responses
Although the two drugs yielded similar results
with respect to heart rate and blood pressure, they

had markedly different effects on cardiac output
(fig. 5). Although not significantly changed by
timolol, cardiac output was reduced 23.1% after five
weeks of propranolol treatment. This result was
somewhat surprising since in Part I of the study
cardiac output was reduced after one week of
timolol therapy. Conclusions regarding the appar-
ent difference between the two drugs should be
regarded as preliminary since cardiac outputs were
obtained in only a small sample of six timolol
patients as. opposed to 11 receiving propranolol.
However, despite the disparity in the size of these
two subgroups, the difference between them was
statistically significant (P < 0.01). The reduction in
cardiac output observed in the propranolol-treated
patients could explain the greater reduction in
systolic blood pressure noted in this group (table

TIMOLOL

PROPRANOLOL

 

6. 65

 

yn WwW fF oO Oo N
T

CARDIAC OUTPUT (L/min)

 

 

 

 

 

 

 

CONTROL Treated
5 weeks

Figure 5

CONTROL Treated
5weeks

Comparative effects of five weeks of continuous administra-
tion of propranolol (11 pts.) and timolol (6 pts.) on cardiac
output,

Circulation, Volume XLVII, July 1973
PROPERTIES OF TIMOLOL

2). Because of the differences in cardiac output
responses, total peripheral resistance fell slightly in
timolol patients, but increased by 21.4% in propran-
olol-treated subjects.

Disturbing side effects including orthostatic
symptoms were not observed in these patients. No
changes were noted in the hemogram, urinalysis,
blood chemistries, electrocardiogram, or chest X-
ray.

Discussion

The present results confirm our previous observa-
tions regarding the activity of MK-950.! Cardiac
output and heart rate are reduced by about 20% and
cardiac sympathetic reflex activity is diminished by
a single oral dose. These effects persist with
continued administration of the drug, although the
cardiac output tends to return to pretreatment
levels over the course of several weeks.

The usual method of evaluating effectiveness of
beta adrenergic blockade is to measure an agent’s
ability to inhibit the effects of isoproterenol
infusion. Isoproterenol, however, is not the normal
cardiac sympathetic stimulator and it seems physio-
logically more correct to assess the degree of
blockade by quantitating responses to reflex sympa-
thetic stimuli. The data from Part I of this study
show that timolol inhibits the blood pressure
overshoot and bradycardia following release of the
Valsalva maneuver; the same has been demonstrat-
ed with propranolol. However, because of difficul-
ty in recording the transient changes the Valsalva
response is not a practical test for clinical use in
assessing the degree of blockade. Inhalation of amyl
nitrite is a more easily applicable test in this regard.
The fall in blood pressure is unaffected by beta
adrenergic blockade, but the reflex tachycardia is
50% inhibited. Similar results can be obtained by
using nitroglycerin instead of amyl nitrite.” It must
be kept in mind, however, that the sympathetic
blockade produced by the available blocking drugs
is not complete and stimuli of sufficient magnitude
such as acute emotional stress or extreme exercise
can overcome it.®: 10

Our data show that timolol possesses antihyper-
tensive activity comparable to that produced by
propranolo]. A reduction in blood pressure is seen
within one week of treatment with both drugs, and
even within the first 24-48 hr in some patients. This
contrasts with the results of Prichard and Gillam‘: ®
who observed that several weeks were required to
obtain an antihypertensive effect with propranolol.
However, these authors began treatment with very

Circulation, Volume XLVI, July 1973

123

small doses of propranolol which were gradually
increased over the course of several weeks until
levels comparable to our initial doses were attained.
If a response is defined as a fall in diastolic pressure
of greater than 6 mm Hg, then 67% of our patients
(8 of 13 on propranolol and 8 of 11 on timolol)
responded. This is within the range of 50-80%
reported in other series employing beta adrenergic
blocking agents.?-® 8 11

The mechanism of the hypotensive action of beta
adrenergic blocking drugs is not known. Prichard
states that there is a “resetting” of the barorecep-
tors? and a central action of beta blockers has also
been postulated.12 Other authors feel that the
decrease in cardiac output is responsible.1*. 14

Although the present study was not constructed
to elucidate the mechanism of the blood pressure
lowering effect of the beta adrenergic blocking
drugs, our data argue against the concept that
reduced cardiac output is the important factor
during long term treatment. Blood pressure was
lowered by the same amount with both drugs, but
cardiac output was reduced only in the propranolol-
treated group. In the nonresponders treated with
propranolol, the cardiac output actually fell further
7.16 liters/min to 5.03 liters/min, than in the
responders who fell from 6.23 liters/min to 5.19
liters/min. In the timolol group neither responders
nor nonresponders changed their cardiac outputs
significantly. It can be concluded from these data
that the hypotensive effect is not related to a
reduction in cardiac output. A similar lack of
correlation between cardiac output and _ blood
pressure has recently been reported by Tarazi and
Dustan. They found that cardiac output was
reduced in 45 of 48 patients, but blood pressure fell
in only 26 patients.§

It is not clear why propranolol produced a
sustained lowering of cardiac output and timolol
did not, especially since the degree of beta blockade
appeared equal. Because of the small number of
patients involved, especially in the timolol group,
additional data should be obtained with timolol in
order to confirm this preliminary observation. Other
observers have found that propranolol tends
to sustain a chronic reduction in cardiac
output. & 18.15 Studies with other beta adrenergic
blocking drugs have yielded results similar to ours.
Practolol does not lower cardiac output to the same
degree as propranolol.’® However, this may be due
to the intrinsic sympathomimetic properties of
practolol which would counteract the negative
inotropic effect of beta blockade.17 Such an
124

explanation does not apply in the present case,
however, since neither propranolol nor_ timolol
possesses intrinsic sympathomimetic activity.

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Circulation, Volume XLVIH, July 1973