Acute and Short-Term Effects of a
New Calcium Antagonist in Hypertension

JAMES F. Burris, M.D., ALDO V. NOTARGIACOMO, B.S., VASILIOS PAPADEMETRIOU, M.D.,
AND EDWARD D. FReIs, M.D.

SUMMARY Nitrendipine (Bay e 5009) is a new calcium antagonist antihypertensive agent similar in struc-
ture and function to nifedipine. Nitrendipine was tested in a range of single and repeated doses in 10 adult
males with uncomplicated mild to moderate hypertension. The treatment goal was reduction of diastolic blood
pressure to 90 mm Hg or less. The dose that achieved goal blood pressure ranged between 10 and 30 mg.
Systolic and diastolic blood pressure began to fall within 15 minutes following ingestion of single oral doses of
nitrendipine. The maximum effect of the drug was achieved in 60 to 90 minutes and remained at approximately
this level for 6 to 8 hours. The average reduction in supine diastolic was more than twice as great as the fall in
systolic blood pressure. With continuous doses given three times daily, all patients’ blood pressures were as low
or lower than the maximal effect observed after single doses. The reduction in blood pressure was sustained for
the full 3 weeks of treatment. There was a sustained smail increase in pulse rate averaging 6 beats/min. The
drug was generally well tolerated by most patients. Mild to moderate headache that resolved with continued
treatment was the most frequent side effect. This preliminary trial indicates that nitrendipine is an effective an-

tihypertensive agent that merits further study. (Hypertension 4 (suppl II): [1-32-H-35, 1982)

nitrendipine Bay e 5009
side effects

KEY WorpDs
diastolic blood pressure

ITRENDIPINE (Bay e 5009) is a new cal-
cium channel blocking agent currently un-
dergoing Phase I testing in the United

States. It is a dihydropyridine derivative with a chemi-
cal structure and mechanism of action similar to that
of nifedipine.’ Previous studies in Germany and
Argentina have indicated that it depresses the slow
depolarizing current, acts as a vasodilator, and causes
a slight increase in cardiac output. It has been
generally well tolerated by patients; headache and
flushing have been the only commonly reported side
effects.

Methods

This study was designed to determine the general
tolerance and activity of nitrendipine in a range of
single and repeated doses. The subjects of the study
were adult males with mild to moderate hypertension
with no evidence of major target organ impairment.
The patients admitted to the trial exhibited supine

 

From the Veterans Administration Medical Center, Washington,
D.C.

Address for reprints: Senior Medical Investigator, VA Medical
Center (151E), 50 Irving Street, N.W., Washington, D.C. 20422.

vasodilators

[1-32

baseline blood pressure (mean of three separate visits)
ranging between a diastolic > 95 and < 115 mm Hg.
The goal of therapy was to lower the supine diastolic
blood pressure to 90 mm Hg or below.

All patients underwent a 3-week baseline evalua-
tion period during which a complete history, physical
examination, and baseline laboratory profile were ob-
tained and weekly measurements of supine and stand-
ing pulse rate and blood pressure were made. If an-
tihypertensive drugs were being taken they were
withdrawn for a 2-week ‘‘washout” period preceding
the baseline period of the study. Pulse rate and blood
pressure were measured at intervals of no more than |
week during the washout period. Baseline laboratory
data included the standard 12-lead EKG, a complete
blood count including a differential and platelet count,
plasma glucose, sodium, potassium, chloride, uric
acid, blood urea nitrogen, creatinine, SGOT, SGPT,
alkaline phosphatase, bilirubin, LDH, CPK, and
urinalysis.

The first five patients recruited into the study were
brought to the laboratory in the morning where they
were given a single oral dose of 5 or 10 mg of nitren-
dipine and observed for 8 hours. Supine and standing
pulse rate and blood pressure were recorded at inter-
vals of 15 minutes for the first hour, then at 30-minute
EFFECTS OF A NEW CALCIUM ANTAGONIST /Burris et al. I-33

intervals for the next 3 hours, and then hourly.
Patients returned at weekly intervals to repeat the
single dosing procedure with progressively larger
doses of nitrendipine until goal blood pressure was at-
tained, intolerable side effects developed, or a max-
imum dose of 30 mg was given. Side effects were
elicited by interview, and EKGs were obtained at each
visit before and after the drug was given. The baseline
blood tests were repeated at least once during the
Single Dose Phase of the study.

After the dose was found that resulted in goal blood
pressure, the patients were given this dose three times
daily as outpatients. Patients were seen 2 days after
beginning the outpatient therapy and then 5 days after
that. Pulse rate and blood pressure were measured at
each visit.

The first five patients continued taking the medica-
tion for an additional 2 weeks, with visits to the clinic
once per week. Five additional patients who met the
same selection criteria as the first group were started
on treatment with 10 mg three times daily. They were
seen 2 days later and if goal blood pressure had not
been attained the dose was increased by 5 or 10 mg in-
crements at intervals of 3 to 5 days until control was
achieved. They then continued taking the medication
for 2 weeks, with weekly clinic visits. Each patient was
seen 2 days after completing the study, for a final
physical examination.

Results

The 10 participants in the study had the following
baseline characteristics, given as means + standard
deviation: age 52 + 6 years, supine systolic blood
pressure 160 + 15 mm Hg, supine diastolic pressure
104 + 6 mm Hg, supine pulse rate 77 + 8 beats/min,
erect systolic pressure 160 + 11 mm Hg, erect dia-
stolic pressure 107 + 7 mm Hg, and erect pulse rate 82
+ 7 beats/min.

Figure | shows the maximum reduction in diastolic
blood pressure achieved by individual patients in the
supine position after single oral doses of nitrendipine.
The magnitude of the antihypertensive effect increased
with increasing doses within the range of dosages used
in this study. The average reduction in supine diastolic
pressure was 29 mm Hg or 28%. The response of the
supine systolic pressure was similar but of lesser
magnitude, that is, 23 mm Hg average fall or a 15%
reduction. Pulse rate in the supine position increased
an average of 9 beats/min above baseline after nitren-
dipine but did not increase progressively with in-
creasing dosage. Similar results were obtained for the
blood pressure and pulse rate recorded in the erect
position. The magnitude of the changes in mean
systolic blood pressure and pulse rate were greater in
the erect than in the supine position. The reverse was
true for the diastolic blood pressure.

The mean percentage reduction in supine diastolic
blood pressure over time for the five patients who
received single doses of nitrendipine is shown in figure
2. The dosage given was that at which individual

 

 

 

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FIGURE 2. Percent reduction in supine diastolic blood

pressure achieved at different times after ingestion of a
single oral dose of nitrendipine {mean + standard
deviation).
I-34 1981 BLOOD PRESSURE COUNCIL

patients achieved the goal diastolic pressure of 90 mm
Hg or less in the supine position. Blood pressure began
to fall within 15 minutes after oral ingestion. The
maximum effect of the drug was achieved in 60 to 90
minutes and persisted for 6 to 8 hours. The reduction
in supine diastolic blood pressure averaged 19%,
which represents a 20 mm Hg fall from the baseline
mean of 105 mm Hg. The reduction of the supine
systolic pressure was again similar but of lesser mag-
nitude, averaging 7% for the group. The reductions in
blood pressure in the erect position were slightly
greater for the systolic and slightly less for the
diastolic blood pressure as compared to the supine
recordings. However, the onset and duration of effect
were the same.

With continuous dosage during the outpatient phase
of the study, the reduction in supine diastolic blood
pressure was nearly the same as that observed follow-
ing single doses. The reduction averaged 16% and was
sustained for the full 3 weeks of treatment without any
evidence of drug resistance (fig. 3). The reduction in
supine systolic pressure averaged 14%, which was
somewhat greater than that attained during the single
dose phase of the study. The reduction persisted for
the full 3 weeks of treatment. Similar reductions in

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FiGure 3. Percent reduction in supine diastolic blood
pressure achieved at different times during continuous out-
patient treatment with nitrendipine (mean + standard devia-
tion).

Supp II, HyperTENSION, Vou 4, No 3, May-June 1982

blood pressure were obtained in the erect position.
There also was a sustained small increase (averaging 6
beats/min) in both the supine and standing pulse
rates. All patients exhibited a reduction in supine dia-
stolic pressure greater than 10 mm Hg on at least one
visit during the outpatient phase of the study. Goal
blood pressure was attained by 90% of the patients,
that is, a supine diastolic blood pressure of 90 mm Hg
or less on at least one outpatient visit, and was at-
tained on all except one outpatient visit by 80%. The
minimally effective dose, that is, the dose at which a
definite reduction in blood pressure was first seen, was
between 5 and 10 mg. The optimal dose, defined as the
dose at which goal pressure was attained, ranged from
5 to 30 mg, with a mean of 17 mg, three times daily.

Side effects reported during the single dose labora-
tory phase were limited to headache in four of five
patients and transient dizziness in one of five. The
headache was frontal, of mild to moderate severity,
and resolved spontaneously in | to 3 hours or sooner
than that following aspirin. During the continuous
dosage outpatient phase of the study, five of 10 pa-
tients reported headaches, one of whom also reported
palpitations. These symptoms usually resolved as pa-
tients continued to take the medication; no patient dis-
continued the drug because of side effects.

One patient while on medication reported the
gradual onset of fatigue on mild exertion, which was
most pronounced in the legs. This symptom disap-
peared after the drug was discontinued at the end of
the study. Subsequent investigation revealed that the
patient had a pre-existing peripheral neuropathy
which may have predisposed him to the development
of this symptom. Another patient developed multiple
symptoms including headache, fatigue, abdominal
cramps, nausea, and constipation. These symptoms
were accompanied by new t-wave inversions in the
lateral precordial EKG leads. There were no eleva-
tions of SGOT, LDH, or CPK in association with
these symptoms. All abnormalities returned to normal
after the medication was discontinued. The greater
severity of symptoms experienced by these two pa-
tients was not correlated with medication dose or
blood pressure response. The first patient was taking
only 5 mg of the drug and still exhibited an excellent
antihypertensive response. On the other hand, the sec-
ond patient was receiving one of the highest doses but
did not achieve goal blood pressure.

Discussion

Calcium channel-blocking drugs inhibit the move-
ment of calcium from the extracellular to the intra-
cellular environment. This results in a reduction in
myocardial contractility and in smooth muscle tone
including the coronary and peripheral arteries as well
as an inhibition of nerve conduction in the heart. Cer-
tain of the compounds, such as verapamil, exhibit in-
creased blocking activity on the cardiac conduction
EFFECTS OF A NEW CALCIUM ANTAGONIST/Burris et al. I-35

system. Nifedipine, on the other hand, exerts a
marked effect on blocking calcium entry into vascular
smooth muscle. Several investigators have found
nifedipine to be highly effective in treating severe
hypertension.2®> Nitrendipine, like nifedipine, is a
dihydropyridine derivative and shares many of the
pharmacological properties of the latter drug. Nitren-
dipine lowers blood pressure in renal hypertensive and
spontaneously hypertensive rats in doses of 0.1 mg/kg
and higher.' In Goldblatt hypertensive dogs, doses of
0.03 to | mg/kg orally were effective. The drug pro-
duced marked vasodilation in the femoral and coro-
nary vascular bed, less in the splanchnic bed, and none
in the vasculature of the skin.’ Nitrendipine thus acts
as a vasodilator with its most marked effect in muscle.

Vasodilator drugs that have their main effect on
arterioles rather than veins, such as hydralazine,
characteristically exert a greater depression of
diastolic than of systolic blood pressure. This is
probably due to the fact that diastolic blood pressure
is dependent primarily on peripheral vascular
resistance, which is greatly reduced with vasodilator
drugs such as nitrendipine. Systolic blood pressure, on
the other hand, is more dependent on cardiac output
than is the diastolic. Since cardiac output charac-
teristically increases after arteriolar dilator drugs are
given, systolic pressure will not fall as much as
diastolic blood pressure.

Phase I clinical trials, such as the present study, can
only provide a preliminary impression of the efficacy
and safety of a new drug. Viewed in that light, the
clinical responses to nitrendipine as an antihyper-
tensive agent appear sufficiently promising to warrant
further investigation.

Summary

Nitrendipine is a new antihypertensive agent similar
in structure and function to nifedipine. In this study it
was effective in reducing supine and standing systolic
and diastolic blood pressure while inducing only a
modest increase in heart rate. Its effect on blood pres-
sure was sustained for the 3 weeks of observation. The
drug was generally well tolerated by most patients.
Mild to moderate headache that resolved with con-
tinued treatment was the most frequent side effect.
This preliminary trial indicates that nitrendipine is an
effective antihypertensive agent. Additional studies
will be needed to clarify its long-term efficacy and tox-
icity.

References

1. Vanov SK: Investigator’s Brochure. BAY e 5009. Vasodilator
and Antihypertensive Agent. Florham Park, New Jersey: Delbay
Research

2. Guazzi MD, Olivari MT, Polese A, Fiorentini C, Magrini F,
Moruzzi P: Nifedipine, a new antihypertensive with rapid action.
Clin Pharmacol Ther 22: 528, 1977

3. Kuwajima I, Veda K, Kamata C, Matsushita S, Curamoto K,
Murakami M, Hada Y: A study on the effects of nifedipine in
hypertensive crises and severe hypertension. Jpn Heart J 19:
455, 1978

4, Beer N, Gallegos I, Cohen A et al: Efficacy of sublinqual
nifedipine in the acute treatment of systemic hypertension.
Chest. In press

5. Guazzi MD, Fiorentini C, Olivari MT, Bartorelli A, Necchi G,
Polese A: Short and long term efficacy of a calcium-antagonist
agent (nifedipine) combined with methyldopa in the treatment of
severe hypertension. Circulation 61; 913, 1980

6. Freis ED, Rose JC, Higgins TF, Finnerty FA Jr, Kelley RT,
Partenope EA: The hemodynamic effects of hypotensive drugs in
man, IV. 1-hydrazinophthalazine. Circulation 8: 199, 1953