Decarboxylase inhibitors in the treatment of hypertension∗

Decarboxylase

Inhibitors

Treatment N.

ALBERT

BREST,

of Hypertension* and

M.D.

the

URING

RECENT

has focused

regulation

it has

of blood

become

actions

YEARS,

of various

their

effect

Thus

it has

alters

both

release.

been

it

that

dopa)

known

decarboxylase cholamine

and

the

present

observations of alpha

report on

to the

FINDINGS

hretylium.

of alpha-methyl-

agent

has

This which

biosynthesis.

newer

monoamine

(alpha

et a1.‘a2 inhibitor

catecholthe

including

the effectiveness

by Oates

Rauwolfia

that by

guanethidine

as a hypotensive

to

catecholamine

3,4-dihydroxy-DL-phenylanine strated

relate

metabolism.

affected

drugs

inhibitors, recently,

is

addition,

agents

and peripheral are

alpha methyldopa was administered to sixteen patients in an initial dosage of 250 mg. twice daily. Thereafter the dosage was increased at biweekly intervals to a maximum of 2,000 mg. per day (500 mg. four times a day). Among these patients, the total duration of therapy ranged from 8 to 18 weeks. Twelve additional subjects were treated with the levoThe maxiisomer of alpha methyldopa (AldometS). mal oral dosage in these patients was 2,000 mg. per day (500 mg. four times a day), and the duration of therapy ranged from 3 to 10 weeks.

in

antihypertensive

demonstrated

central

antihypertensive More

the

catecholamine

activities

oxidase

that

hypotensive

on

Likewise

amine

In

pressure.

evident

It

is

discuss

been

demon-

reduction

depresses our

antihypertensive

al!ha

hypertensive

compound the

Parmteral

methylis a cate-

purpose

after

blood

preliminary

cases,

abilities

not

however,

however, AND

METHODS

Parenteral alpha Methyldopa: The racemic mixture of alpha methyldopa was administered intravenously to fifteen hospitalized patients whose blood pressure was greater than lSO/lOO mm. Hg. Dosages varying from 100 to 3,000 mg. were diluted in 100 cc. of 5 per cent glucose in water and infused over a 15 minute The blood pressure response was measured, interval. with the patient in the supine and upright positions, every 5 minutes during the period of infusion and every 15 minutes thereafter for at least 6 hours. Ornl a&ha Methyldopa: Twenty-eight ambulatory patients whose blood pressure was greater than 150/100 mm. Hg were randomly selected from the Hypertension Out-Patient Clinic. After an initial diagnostic evaluation, the subjects were placed on placebo medication for a minimal period of 3 weeks. They returned to the clinic at weekly intervals, and blood pressure and physical signs and symptoms were recorded. After the control period, the racemic mixture of * From the Hypertension-Renal

Unit, Hahnemann

an for

patients

(despite was

the fact

Drowsiness

sisted

up to 24 hours

Oral alpha

after

mean

arterial

than

20

mm.

Hg

two

of the

blood the

three

pressure upright

significant

in

was position,

response

normotensive

included

palpitations

(five

patients)

the

patients

obtained

pressure

supine

five

with

the

of the

and When

patient

in

obtained

a

five

became

The

side

reactions

drowsiness

(six

patients),

I).

orthostatic

headache

(three

a

of more

position,

patients

two

patients), and

infusion.

normotensive.

taken

fif-

and per-

sixteen

three

blood

and

(Table

encountered (four

a single

became

in blood

ten of the

profound

racemate,

in

of the fifteen

reduction

Of the

was only

drowsiness;

in only

was often

the

effect The

hours. was

that

Metfyldopa:

with

was susIn other

1).

in each

accomplished

teen).

drop

and

(Fig.

occurred

the

2 to 4 hours

injection hours

encountered

pressure

fifteen

significant

antihypertensive

this effect

treated

within

12 or more

reaction

side

began

2 or more

obtained

a

In most instances

pressure.?

intravenous

for

of the

obtained

response

the

tained

of

Ten

MetfzyLdofia:

subjects

hypotensive

methyldopa. MATERIALS

F.A.C.C.

M.D.,

Pennsylvania

iIICP2aSing ZittentiOn

on the role of catecholamines

H. MOYER,

JOHN

Philadelphia,

D

in the

weakness patients).

t A reduction in mean arterial blood pressure (diastolic pressure plus one-third the pulse pressure) of 20 mm. Hg or more was considered significant.

Medical 116

Collegr and Hospital,

Philadelphia,

THE AMERICANJOURNAL

Pennsylvania. OF CARDIOLOGY

Decarboxylase Alpha-Methyl Dopa 500 mg (I.V.) $4

Inhibitors yo

in Treatment

within 1 week after discontinuation of the drug. Three of the twelve patients treated with the levo-isomer (Aldomet) obtained a drop in mean arterial blood pressure of more than 20 mm. Hg in the supine position, and two of the three became normotensive. When the blood pressure was taken with the patient in the upright position, five patients obtained a significant response and three of the five became normotensive (Table II). The side reactions in this group included drowsiness (five patients), orthostatic weakness (one patient) and headache (one No toxic reactions were encountered. patient).

Medicatioy

Pt. EM.

D

BO-

s d

60-

DAY

^

2

COMMENTS

supine Upright

C---.

40

t

Co”+rol

9AM

IO

,I

12noon

2

3PM

9AM

117

of Hypertension

12nwn

3

FIG. 1.

Blood pressure response to intravenous alpha methyldopa. Significant blood pressure reduction began two hours after intravenous injection of alpha methyldopa. The antihypertensive effect was sustained for more than 8 hours.

a maculopapular skin eruption In addition, The rash was pruritic occurred in one instance. and involved both the trunk and extremities; however, the eruption cleared spontaneously

According to the theory of Blaschko,3 the biosynthesis of norepinephrine proceeds, at least in part, from the conversion of dihydroxyphenylalanine (dopa) to dopamine to norepinephrine (Fig. 2). Blaschko3 further suggests that the enzyme, dopa decarboxylase, catalyzes Therethe conversion of dopa to dopamine. fore, it may be postulated that the production of norepinephrine can be depressed by an inhibiThis tion of dopa decarboxylase activity. postulate has been confirmed by the finding that alpha methyldopa is an effective inhibitor of aromatic amino acid decarboxylation in man.l It is the opinion of Udenfriend et a1.4 that a single enzyme is responsible for the decarboxylation

TABLE I Blood Pressure Response to Oral Alpha Methyldopa

Patient

Maximal Dosage * (mg.)

Age hr.1 Sex and Race

(D, L)

-

Duration of Treatment (wk.)

Supine

dear

Erect

dear

Supine

dear

Erect

Ptiean

8 8 10 11 18 14 8 8 8 10 8 8 10 8 16 8

180/110 196/108 236/146 210/110 150/106 215/108 150/100 180/110 150/104 182/130 158/106 208/108 170/118 212/110 172/100 224/110

133 137 176 143 120 144 117 133 119 147 123 141 135 144 124 148 -

200/120 184/110 200/140 200/120 150/100 230/l 16 154/110 190/110 150/112 152/120 158/110 190/100 158/116 200/106 194/112 220/124

147 135 160 147 117 154 125 137 125 131 126 130 130 137 133 156 -

205/l 30 200/l 10 234/l 24 170/104 128/82 180/94 160/104 166/94 162/106 186/126 160/104 184/94 110/70 210/100 176/100 208/108

155 140 161 126 97 123 123 118 125 146 123 124 83 137 125 141 -

210/130 190/114 214/122 148/108 112/80 182/108 160/110 170/102 160/116 182/132 160/110 190/100 120/80 196/104 162/100 186/106

157 139 153 121 91 133 127 125 130 149 127 130 93 135 121 133

Control Blood Pressure (mm. Hg)

Blood Pressure after Treatment (mm. Hg)

-_ 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

L. B. F. M. C. T. H. A. S. B. L. Y. F. C. w. M. c. w. M. H. I. c. M. L. B. D. W. B. L. E. S. E.

62, 65, 34, 52, 64, 51, 66, 52, 53, 42, 33, 72, 35, 56, 32, 41,

F, N F, N F, N M, N M, N F, N F, N F, N M, N M, N F, N F, W F, N M, N F, N F, W

* Total dosage per day JANUARY 1962

1,500 2,000 2,000 2,000 2,000 2,000 1,500 2,000 2,000 2,000 1,000 2,000 1,000 2,000 1,000 1,000

-

Brest

118

and

Moyer

TABLE II Blood

T. R. 0. W. L. F. S. R. A. H. R. H.

Sex and Race

M. S. c. B. E. M. E. D. D. L. B. A.

62, 55, 60, 59, 32, 70, 41, 55, 65, 43, 60, 52,

Dosage* (mg.)

M, W M, N

M; W M, F, F, F, M, F, F, M, M,

N N N N W N N N N

* Total

dosage

Response

Duration of Treatment

Age hr. ), Aiiaximun

Patient

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Pressure

1,500 2,000 1,500 2,000 2,000 2,000 1,500 1,500 2,000 2,000 2,000 1,500 -

to Oral

Control

Alpha

Blood (mm.

Methyldopa

T

Pressure

Blood

Hg)

(wk.)

Supine

bvfear

Erect

4 3 3 10 10 8 6 4 8 8 8 10

200/120 210/130 210/110 220/100 170/100 195/105 195/115 175/110 195/105 160/120 170/120 175/110

147 157 143 140 123 135 142 132 135 133 137 132 L L

180/110 220/140 200/l 10 220/120 175/110 185/110 195/120 170/115 185/110 160/120 175/135 175/120

-

(L)

-i133 167 140 153 132 135 145 133 135 133 148 138

Pressure

after Treatment

(mm.

Hg)

Supine

vkar

Erect

dean

170/90 250/140 140/90 190/100 185/100 220/l 15 200/l 10 160/100 175/95 1601115 190/115 130/80

117 177 107 130 128 150 140 120 122 130 140 97 -

140/80 240/130 140/80 185/110 175/110 205/115 195/110 140/100 150/90 165/115 165/125 120/85

97 167 97 135 132 145 138 113 110 132 138 97

-

I -

-

per day.

of various aromatic amino acids including dopa, 5-hydroxytryptophan (5-HTP), tryptophan, phenylalanine and tyrosine. Dengler and Reiche15 showed that prior administration of alpha methyldopa to cats blocked the pressor effect of dopa. Westermann6 and co-workers found that the decarboxylase inhibitor blocked the bronchoconstrictor action of 5-HTP in guinea pigs; Goldberg et al.’ showed that alpha methyldopa reduced the cardiostimulatory effect of dopa in dogs. Oates et al.’ demonstrated that alpha methyldopa was an effective decarboxylase inhibitor They found that oral administration in man. of the drug reduced the urinary excretion of amines derived from “loading” doses of 5-HTP, tyrosine and tryptophan. Sjoerdsma et a1.8 subsequently reported that alpha methyldopa administered to patients with carcinoid resulted in an increased excretion of 5-HTP (precursor of serotonin) and a decreased excretion of 5-hydroxyindole acetic acid (excretion product of serotonin), thus emphasizing that the drug effectively inhibits decarboxylase activity in man. The potential antihypertensive effectiveness of alpha methyldopa was also confirmed by Oates and co-workers.‘v2 They reported blood pressure reduction, predominantly orthostatic, in ten hypertensive subjects treated with the oral form of the drug. In their studies, alpha methyldopa was administered in dosages of 1

to 6 gm. per day for periods ranging from 7 to 28 days. Sjoerdsma” subsequently reported that levo-isomer accounted not only- for all the decarboxylase blocking effects, Ijut also for the hypotensive effects as well. The antihypertensive action of alpha methyldopa was also evident in the present study. Significant blood pressure reduction was accomplished with the parenteral drug in ten of fifteen hypertensive patients. Although the antihypertensive action was less prominent with the oral drug, it is likely that a greater response could have been achieved with larger oral doses. In this regard it is notable that oral absorption studies indicated that less than 20 per cent of the dose of alpha methyldopa is absorbed from However, because of the the intestinal tract.‘O preliminary nature of the current investigation and the specific intent to study pharmacodynamics within a limited range, oral dosages greater than 2 gm. were not employed. Although it seems logical to assume that the hypotensive effect achieved with the decarboxylase inhibitors is related to the inhibition of catecholamine biosynthesis, this assumption has not been confirmed thus far. The ability of alpha methyldopa to lower catecholamines in tissues of various species”“2 has focused attention on this action primarily because, as described previously, different groups of antihypertensive agents (including Rauwolfia, guanethidine and bretylium) affect catecholamine THE

AMERICAN

JOURNAL

OF CARDIOLOGY

Decarboxylase

Inhibitors

in Treatment

TYROS/NE

-$-;H-COOH s

of Hypertension

119

dynamic mechanism, i.e., inhibition of decarboxylase activity with secondary depression of norepinephrine biosynthesis. It is as yet uncertain, however, whether this inhibitory effect accounts for the antihypertensive response obtained. Although further investigations are necessary, it is hoped that these new agents will ultimately enhance the antihypertensive armamentarium. REFERENCES

OOPA (3,4-dihydroxyphenylolonine)

.

OOA i&E

(3,4-dihydror

;y,phenylethylomine) * -;-NH,

NOREF/NEPHi?/AfE FIG. 2. Biosynthesis of norepinephrine. The enzyme, catalyzes the conversion of dopa to decarboxylase, dopamine.

in contrast with these activities. However, drugs, alpha methyldopa does not interfere with different sympathetic transmission. Thus, Stone et all3 reported that alpha methyldopa administered parenterally or orally in doses of 100 mg. of the levo-isomer per kilogram or more did not result in overt relaxation of the nictitating membrane of dogs nor cats. Likewise, in anesthetized dogs, alpha methyldopa did not interfere with reflex pressor responses elicited by central vaga1 stimulation or bilateral carotid occlusion. Pharmacologically, in laboratory species at least, alpha methyldopa is distinctly different from guanethidine, bretylium and Rauwolfia, all of which block efferent sympathetic nerve transmission. SUMMARY Clinical observations with a new antihypertensive agent, alpha methyldopa, are reported. The drug possesses a rather unique pharmaco-

JANUARY1962

1. OATES, J. A., GILLESPIE, L., UDENFRIEND,S. and SJOERDSMA, A. Decarboxylase inhibition and blood pressure reduction by alpha-methyl-3,4dihydroxy-DL-phenylalanine. Science, 131 : 1890, 1960. 2. OATES, J. A., GILLESPIE, L., CROUT, J. R. and SJOERDSMA, A. Inhibition of aromatic amino acid decarboxylation in man and associated pharmacologic effects. J. C&n. Invest., 39: 1015, 1960. 3. BLASCHKO, H. The development of current concepts of catecholamine formation. Pharmacol. Rev., 11: 307, 1959. 4. UDENFRIEND,S., LOVENBERG, W. M. and WEISSBACH, H. L-amino acid decarboxylase activity in mammalian tissues and its inhibition by alphamethyl dopa. Fed. PTOC., 19: 7, 1960. 5. DENGLER, H. and REICHEL, G. Die Beeinflussung der Blut-druckwirkung von Dopa und Dops durch einen Decarboxylase Inhibitor. Arch. Exper. Path. u. Pharmnkol., 232: 324, 1957. 6. WESTERMANN, E., BALZER, H. and KNELL, J. Hemmung der Serotoninbildung durch AlphaMethyl Dopa. Arch. Exper. Path. u. Pharmakol., 234: 194, 1958. 7. GOLDBERG, L. I., DACOSTA, F. M. and OZAKI, M. Actions of the decarboxylase inhibitor, alphamethyl-3,4-dihydroxyphenylalanine, in the dog. Nature, 188: 503, 1960. 8. SJOERDSMA,A., OATES, J. A., ZOLTZMAN, P. and UDENFRIEND,S. Serotonin synthesis in carcinoid patients. New England J. Med., 263: 585, 1960. 9. SJOERDSMA, A. Reported at American Heart Association High Blood Pressure Research Council Meeting, Cleveland, October 1960. 10. GILLESPIE, L. Clinical pharmacology of newer antihypertensive agents, monoamine oxidase and decarboxylase inhibitors, bretylium tosylate, and guanethidine. Ann. New York Acad. SC., 88: 1011, 1960. 11. PORTER, C. C., TOTARO, J. A. and LEIBY, C. M. Effect of decarboxylase inhibitors on serotonin and catecholamine levels in mice. Pharmacologist, 2 : 81, 1960. 12. HESS, S. M., OZAKI, M. and UDENFRIEND,S. Effects of a-methyldopa and a-methyl metatyrosine on the metabolism of serotonin and norepinephrine. Pharmacologist, 2 : 81, 1960. 13. STONE, C. A., PORTER, C. C., WATSON, L. S. and Ross, C. A. Pharmacology of decarboxylase in inhibitors. In : Hypertension : Recent Advances. Philadelphia, in press. Lea & Febiger.