Antihypertensive Therapy

EDWARD D. FREIS

Veterans Administration Hospital, Washington 7, D. C.

Effective antihypertonsive drug therapy began
with the ganglion-blocking agents, followed by
reserpine and hydralarine. later advances in-
cluded the benzothiadiazine saluretic agents
and more recently compounds which specifi-
cally inhibit the sympathetic nervous system,
such as guanethidine, alpha-methyldopa, and
certain amine oxidase inhibitors.  Among the
antihypertensive drugs, molecular modifications
seem to have yielded the greatest clinical bene-
Qts in the period immediately following the
discovery of an agent with a new type of ac-
tion.  Further improvements have been limited
because of inability to circumvent objection-
able side effects which were indissolubly linked
with the mode of antihypertensive action of a
given class of compounds.

I t is remarkable that effective antihypertensive agents have been developed
entirely during the past 15 years. The thread which ties together this period
of therapeutic progress has been based on a continuous interchange of informa-
tion between the clinic and the chemical laboratory, in which specific therapeutic
needs have motivated the direction of chemical development.  This paper dis-
cusses the manner in which new compounds lead not only to therapeutic ad-
vances but also to fresh problems.  It also indicates how molecular modifications
have been used sometimes successfully, sometimes fruitlessly, to meet the con-
tinuing demands of the clinician.

Ganglion-Blocking Agents

  The main path of development of antihypertensive agents began with the
observation that tetraethylammonium chloride inhibited the transmission of
nerve impulses through sympathetic ganglia in both animals and man and
transiently lowered blood pressure in hypertensive patients (12). Paton and
Zaimis (15) then proceeded to investigate a series of quaternary ammonium
salts in which varying numbers of methylene groups were interposed between

67


68                 MOLECULAR MODIFICATION IN DRUG DblGN

two trimethylammonium cationic heads. The higher members of the series,
such as decamethonium, were found to have a curare-like action-that is, they
produced paralysis of voluntary muscle. The compounds with fewer methylene
groups produced ganglion-blocking action; hexamethonium appeared to be the
most effective and was found to be a potent antihypertensive agent.  It repre-
sented the first clinically practical drug treatment for severe hypertension
(6, 16).  The reversals of malignant hypertension to a more benign phase of
the disease were so dramatic that they revolutionized the methods of treating
hypertension which, until that time, had been dominated by surgical sym-
pathectomy and low-salt diets.

  There were, however, many undesirable features related to hexamethonium
treatment.  The drug was not very effective or predictable in its action when
given by mouth, unless the doses were pushed to high levels and, at these high
doses, severe side effects could occur. Paralysis of the bowel was a particularly
dangerous reaction when large doses had been given orally, since a large amount
of the drug remained in the intestinal tract, prolonging and aggravating the
toxic effect.  Because of poor absorption, the drug was given by injection in
most cases, in the same manner as insulin in a diabetic.  An unusual toxic reac-
tion associated with hexamethonium was pneumonic infiltration of the lung,
which was not seen with the blocking agents developed later.

  Because of potentially severe toxicity and the need for parenteral injections,
pharmaceutical research was directed toward developing ganglion-blocking
agents which would be less toxic and could be effectively administered orally.
Such a drug, another diquatemary ammonium salt, was soon discovered and
was given the name of pentolinium tartrate (7, 20).  There was no doubt that
pentolinium, or Ansolysen, represented a considerable improvement over hexa-
methonium. It was more potent, much more effective by mouth, and somewhat
longer acting, and caused no pneumonitis and far less paralysis of the bowel.
It quickly replaced hexamethonium as the treatment of choice in severe hyper-
tension.

  Pentolinium, however, had certain disadvantages which made it impracti-
cal for the treatment of mild or moderate hypertension.  The disturbing side
effects associated with blockade of the sympathetic and parasympathetic
nervous system were still present:  constipation, dry mouth, impotence, chilling
in a cold environment, and blockade of the reflex adjustment of blood pressure
which normally occurs when the patient assumes the erect position.  Occa-
sionally, the postural hypotension was so severe that there was insufficient blood
flow to the brain and the patient fainted.

  Another feature of all ganglion-blocking drugs was that the blood pressure
fluctuated considerably from very low to high values.  Despite careful adjust-
ment of the dose, this fluctuation could not be done away with entirely.  In the
attempt to prevent the peaks of pressure the doses were elevated so that the
patient at another time might be unable to stand erect because of postural
hypotension.

  Quatemary ammonium bases are poorly absorbed from the gastrointestinal
tract. In the case of hexametbonium and pentolinium less than 10% of the
ingested dose is actually absorbed.  Further development of effective ganglion-
blocking agents, therefore, was directed toward improving absorption.  It was
hoped that the fluctuations in blood pressure and the severity of the side effects


6.  FREIS   Antihypertensive Therapy                      69

associated with pentolinium would be overcome if the blocking agent was
completely absorbed.

This reasoning led to the development of mecamylamine by Stone and his
associates (19). Mecamylamine is not a quatemary base but rather a second-
ary amine which permits complete absorption from the gastrointestinal tract.
This modification unfortunately did not strikingly improve therapeutic effective-
ness (8). Clinical trials soon showed that the fluctuating blood pressure re-
sponse associated with the ganglion-blocking agents was not due primarily to
variable absorption.

Saluretic Agents

This clinical experience with mecamylamine made it clear that the cause
of the variable responsiveness to the ganglion-blocking drugs was not poor
absorption but rather changes in the responsiveness of the patient's blood pres-
sure to ganglionic blockade. A most important factor was the state of hydration,
or amount of salt and water in the body (5). When patients became edema-
tous they required larger doses of blocking agents to lower their blood pressures,
and the blood pressure was more difficult to control even with the larger dose.
Thus, accumulation of salt and water, leading to expansion of extracellular fluid
volume, produced increased resistance to the antihypertensive effects of gang-
lion-blocking drugs. Contrariwise, mercurial diuretics or salt-depleting diets
made patients more responsive to these blocking agents. Furthermore, salt-
depleting procedures lowered blood pressure moderately in hypertensive
patients even in the absence of other drugs. These observations led to the
next major development in antihypertensive therapy: the discovery of practical
agents for inducing and maintaining a state of moderate salt depletion in
hypertensive patients.

This development came about through a series of molecular modifications
which began with the basic observation that certain sulfonamide drugs inhibit
the enzyme carbonic anhydraw. The diuretic acetazolamide was one practical
result of such investigations.

In a systemic program of molecular modification of the benzenedisulfonam-
ides, Novello and Sprague, in collaboration with the pharmacologists Baer and
Beyer, observed an unexpected high order of diuretic activity in such com-
pounds as benzene-1,3-disulfonamide (17). Their investigation led eventually
to cyclic compounds, of which chlorothiazide appeared to be one of the most
active. Chlorothiazide was only a weak carbonic anhydrase inhibitor and its
mode of action was not the same as that of either the mercurials or acetazol-
amide. However, chlorothiazide was well absorbed after oral administration and
was effective in causing sodium excretion in hypertensive patients.  The
initial antihypertensive effect of the drug appeared to be accompanied by a
reduction of plasma volume associated with the saluretic effect (5).

  Certain side reactions are associated with long-term treatment with
chlorothiazide. The most common side effect is a reduction in serum potassium
concentration. There is also an elevation in serum uric acid concentration,
occasionally with precipitation of acute attacks of gout.  In rare instances,
hyperglycemia and diabetes mellitus have occurred. Numerous molecular
modifications have since been made, with the hope of producing a compound


70                 MOLECULAR MODIFICATION IN DRUG DESIGN

that would retain the sodium diuretic effect but not induce potassium loss or
uric acid retention. Despite considerable work, these efforts have not succeeded
in developing an agent with significantly improved clinical usefulness.

  Hydrogenation of the chlorothiazide molecule led to hydrochlorothiazide,
which permitted the dose to be reduced tenfold, but the only practical ad-
vantage was that the patient took less drug.  This, and various other modifica-
tions of the basic compound, led to insignificant changes in electrolyte excretion
ratios which were of little practical value clinically.

  A compound of somewhat related structure, chlorthalidone, is of interest
because of its long duration of action and considerable potency (13).  A con-
venient single-dose-per-day schedule is sufficient to induce and maintain an
adequate natriuresis.  At times, some of our patients seem to become tolerant
to chlorothiazide and transferring their medication to chlorthalidone again in-
vokes a saluretic effect. However, chlorthalidone induces the same hypokalemia
and hyperuricemia that has been so frequently observed during long-term
treatment with the benzothiadiazines.

  An interesting new development has been the discovery that certain
pteridine compounds promote sodium excretion and, at the same time, potas-
sium retention.  Clinical studies in hypertensive patients carried out with
triamterene indicated that the drug was not in itself sufficiently potent as a
natriuretic agent in hypertensive patients to be clinically useful (10).  When
combined with half-strength doses of hydrochlorothiazide, however, its natriur-
etic effect was comparable to that obtained with full doses of hydrochloro-
thiazide but without significant urinary loss of potassium or reduction in serum
potassium concentration.  Thus, triamterene may represent a beginning in the
development of new compounds with more specific natriuretic properties.

Adrenergic Blocking Drugs

  With the combined use of chlorothiazine and ganglion-blocking agents, the
chemotherapeutic method for controlling severe hypertension became firmly
established. The disturbing side effects produced by the ganglion-blocking
agents, however, remained a definite nuisance. Patients complained not only of
side reactions produced by sympathetic blockade, such as weakness and faint-
ness in the erect position due to postural hypotension, but also of parasym-
pathetic blocking effects which included constipation, dryness of the mouth,
failure of visual accommodation, difficulty in emptying the urinary bladder,
and impotence. Therefore, a search was made for compounds which would
block the sympathetic system selectively, leaving parasympathetic functions
undisturbed.

  As a result of this search, a number of new compounds with interesting
properties have been developed.  These include bretylium tosylate (2),
guanethidine (14)) methyldopa [3- (3,4-dihydroxyphenyl) alanine] (18)) and
pargyline (11) .  AU these compounds produce a more selective inhibition of
the sympathetic nervous system, although each differs somewhat one from the
other, in both primary mode of action and clinical effects. Of these compounds,
guanethidine has received the most extensive therapeutic trial and clinical
acceptance.

Guanethidine was the outgrowth of certain pharmacological observations


6.  FREIS   Antihypertensive Therapy                       71

made by Maxwell, Plummer, and coworkers, on compound SU-4029 (14) I
SU-4029 antagonized the pressor effects of amphetamine and ephedrine,
blocked the carotid occlusion pressor reflex, and lowered blood pressure in
neurogenic and renal hypertensive dogs.  The duration of action was remark-
ably prolonged over a period of several weeks.  SU-4029 produced disturbing
side reactions in clinical trials but guanethidine did not, thus providing another
example of successful molecular modification.
  Guanethidine lowers blood pressure in hypertensive patients by reducing
both cardiac output and total peripheral resistance (4). There also is some
redistribution of blood %ow, so that less of the cardiac output is distributed to
the intestines and liver. When guanethidine is given to patients intravenously,
there is a transient period of elevation of cardiac output and rate and blood
pressure, suggesting that catecholamines have been released (4). The dura-
tion of action of the drug in man appears to be about one week, SO that doses
taken daily tend to be cumulative over that period (9). As with the ganglion-
blocking drugs, the effective hypotensive dose varies widely from one patient
to another, and the saluretic agents enhance the antihypertensive effects of
guanethidine. The side effects are considerably less than with the ganglion-
blocking agents and the blood pressure seems to fluctuate to a lesser degree.
  The newer antihypertensive agents, of which guanethidine is one example,
represent an outgrowth of current concepts of catecholamine metabolism.  It is
now believed that norepinephrine is stored in the form of granules in the
sympathetic nerve endings (3). Under adequate stimulation, the norepineph-
rine is released to constrict the smooth muscle of blood vessels or increase the
force of contraction of the heart, thereby raising blood pressure. Certain pressor
amines such as tyramine and ephedrine are believed to act in this fashion by
releasing the norepinephrine stored in the nerve endings.  Reserpine, an anti-
hypertensive agent that we have not yet discussed, produces depletion of the
norepinephrine stores (3). Guanethidine may also act in somewhat the same
fashion, although the clinical effects of guanethidine and reserpine are different.
Although guanethidine may produce some release of catecholamines on intra-
venous administration, the exact mechanism of action of this drug has not been
clarified, except that it produces some sort of a peripheral block of the SW-
pathetic nervous system (14).
  Methyldopa was synthesized for the purpose of inhibiting the decarboxyla-
tion of dopa to dopamine, which is believed to be the precursor of norepine-
phrine (18). Thus methyldopa should prevent the formation of catecholamine
stores. It seems probable that the mode of antihypertensive action of methyl-
dopa is more complex than simple inhibition of norepinephrine synthesis.
Clinically, the drug lowers blood pressure with less prominent orthostatic hy-
potension than guanethidine. However, some patients seem to be resistant
to the drug and it is not generally dependable in reducing blood pressure as is
guanethidine (Figure 1) .
  It has been known for some time that monoamine oxidase inhibitors will
lower blood pressure in hypertensive patients and produce orthostatic hypo-
tension.  Theoretically, by preventing the metabolic degradation of norepi-
nephrine, such compounds should raise blood pressure by increasing catechol-
amine stores.  However, these enzyme inhibitors also have other actions, in-
cluding a ganglion-blocking effect. Early trials with monoamine oxidase inhibi-


72               MOLECULAR MODIFICATION IN DRUG DESIGN

J.S. 42d Fundi II -BUN IS-LVH

YOROTON Kx)mg daily

Figure 1. Effect of alpha-methyldopa and chlorthulidone (Hygroton)
compared to guanethidine plus chlorthalidone in patient with hyperten-
             sion resistant to treatment

Vertical dashed lines indicate blood pressure readings taken while patient was
standing in erect position.  Alpha-methyl-do
in this patient, but did not produce ;$omsy P a did not control blood pressure
                   hypotewion seen with guanethi-

tors in the treatment of hypertension were disappointing because of the de-
velopment of toxic reactions associated with the hydrazine group.  More re-
cently, pargyline, which does not contain a hydrazine, has been shown to exert
monoamine oxidase activity and also to be a potent antihypertensive drug (11) .
Clinical experience con6rms the active antihypertensive effect, including ortho-
static hypotension. Final evaluation of pargyline and alpha-methyldopa as
antihypertensive agents must await more extensive clinical trials.

Other Antihypertensive Agents and Combinations

This survey would not be complete without mentioning the Veratrum
alkaloids (whose use is limited because of their emetic effect) as well as
hydralazine and reserpine. Both of these latter agents still hold a prominent
place in the clinical management of patients with hypertension.  The placebo-
controlled double-blind studies carried out in the Veterans Administration Co-
operative Study on Antihypertensive Agents (1) indicated that hydralazine


6.  FRHS   Antihypertensive Therapy                       73

m PLACEBO
m CHLOROTtllAZlOE I. 0 gm /day
m RESERPINE 0.5mg /day
- CHLOROTHlAZlOE -I- RESERPlNE

          RESERP. i HYDRALAZINE -2OOmg/day
        CHLOROTHIAZIDE + HYDRALAZlNi

CtRtH

         I     I     I     I     I
+4 0 -4 -6    -12    -16   -20
    AVERAGE CHANGE - DIASTOLIC B.P. - mm Hg

Figure 2.  Results of Veterans Administration Cooperative
     Study on Antihypertensive Agents
Each bar represents average of large group of patients with mild
and moderate hypertension, and refers to change in diastolic
pressure from pretreatment hospital control values to 3 months
             posttreatment

and reserpine are most effective when combined with each other or with a
saluretic agent.

Whereas there was a slight rise in the average diastolic blood pressure of
the group of patients in the VA study receiving only placebos, there was a
slight reduction in the groups receiving chlorothiazide alone or reserpine alone
(Figure 2).  In the patients who received chlorothiazide plus reserpine the
reduction was approximately twice that obtained with either drug alone.
Similar reductions in blood pressure were obtained with the combination of
reserpine and hydralazine, or chlorothiazide and reserpine, while the admin-
istration of all three agents resulted in a highly significant blood pressure
reduction.

  Such results indicate that in the present state of development of anti-
hypertensive drugs any new compound, which in itself may not be sufficiently
potent to be relied upon for adequate blood pressure control, may still be
clinically useful if its mode of action is different from previously known agents
and it does not cause disturbing or dangerous side effects.  Such new agents
may be useful in combination with other drugs, as shown in the Veterans
Administration Cooperative Study.

Conclusions

  The most successful programs of molecular modification seem to have
included recognition of clinical need and willingness to explore new approaches
in answer to therapeutic problems.  Among the antihypertensive agents,
molecular modification of existing compounds has been most effective in the
period immediately following the discovery of an agent with a new type of


74                MOLECULAR MODIFICATION IN DRUG DESIGN

action. Improvement beyond a certain point is prevented by inability to over-
come clinically undesirable characteristics associated with the basic mode of
action of a particular class of compounds.  Early recognition of this point of
diminishing returns should avoid unnecessary expenditure of time and effort.

Literature Cited

(14) Maxwell, R. A., Plummer, A. J., Schneider, F., Povalski, H., Daniel, A. I., J.
PharmacoE. Exptl. Therap. 128,2 ( 1960).
(15) Paton W. D. M., Zaimis, E. G., Nature 162,810 (1948).
(16) Restah, P. A., Smirk, F. H., New Zealand Med. J. 49,206 ( 1950).
( 17
(18  Sprague, J. M., Ann. N. Y. Acad. Sd. 71,328 (1958).
  Stone, C. A., Porter, C. C., Watson! L.,;S., Ross, C. A., "H pertension. Recent
+f&;nces. Second Hahnemanu Syrnposmm, p. 417, Lea & Fe 6 iger, Philadelphia,

----.

(19) Stone, C. A., Torchiana, M. L., O'Neill, G. P., Beyer. K. H., Proceedings of Am.
Sot. Pharmacology and Therapy, Iowa City, Sept. 7,1955.
(20) Wein R., Mason, D. F. J., Lancet 1,454 (1953).
RECEIVED December 9,1963.

Discussion

                    C. 1. CAVALLITO, presiding
  Dr. John Holly (Ottawa) :  I would like to direct one question to Dr.
Page. There is a general feeling, I know, among a number of clinicians, that
women can tolerate an elevated blood pressure better than men.  Does he
believe this is statistically true, and why?
  Dr. Page: I think the answer is probably yes, but not on a statistical basis.
They do it on the basis that they cut a much better figure than we do as males.
You have to face the fact that the battle of the sexes has long since been won by
the female. She has a longer life span, she is a healthier person, and she is nm-
ning things anyway.

  So if you think it is a man's world, remember it is in your wife's name.
  Dr. Louis Friedman (U. S. Vitamin) :  Is it due to hormonal differences?
  Dr. Page: I suspect it is, but I have not the slightest idea'which hormone.
You see, there is supposed to be a difference between femininity and being a
woman and this is a distinction which I hesitate to bring up with my wife.


Cardiovascular Disease

75

  Dr. Cavallito:  I would like to ask Dr. Freis if it would be fair to conclude
from his presentation that although in numerous instances molecular modifica-
tion has not led to a significant improvement, yet there have been cases of
definite improvemenrt. Do you think this is a reasonable assessment of the past
ten or fifteen years?
  Dr. Freis: Yes. I tied to give some examples of that. The modtication
of SU-4029, which was not very successful clinically, led to guanethidine which
was a most successful modification, whereas a great deal of work went into
modifying thiazides and most of this has not led to any great practical advan-
tage.  The same could be said for the ganglionic blocking drugs after pento-
linium tartrate had been developed.
  Dr. Cavallito:  Would it also be fair to say that one would not know this
in advance of implementing the molecular modifications?
  Dr. Freis: I do not know about that. I would think one would have
guessed after about the first 50 modifications of chlorothiazide and those that hit
the market, that further modifications might not be of any great value.  That
could have been said of the benzothiadiazines, and of the ganglionic blocking
agents.

  There is a tendency to proceed on one line a little long in pharmaceutical
research. This may be profitable; I do not know.  But it is not scientifically or
therapeutically very profitable. I think there is a time to quit.
  Dr. Cavallito:  I have one more question, and in leading up to it, I would
like to show one illustration.

  I recall that ten or fifteen years ago one of the questions was: Is it really
useful to lower blood pressure?  The consensus at that time seemed to be that
you had better leave it alone.  For a talk presented in mid-1955, I was in-
terested in getting some reflection of the amount of interest in hypertension and
its therapy, and plotted as a reflection of interest the number of publications
that appeared per year, covering the chemistry, pharmacology, and clinical as-
pects of hypertension.  Using the same general background of available litera-
ture, this chart shows clearly the rapid increase in interest in hypertension and
its therapy as reflected by the literature.

                    NUMBER OF PUBLICATIONS

  I would like to ask Dr. Freis if he feels that therapy or treatment of hyper-
tension is really useful, from the standpoint of the patient's well-being and
ultimate life expectancy.
  Dr. Freis: I think that it has been proved that in malignant hypertension
YOU can prolong the lives of many patients and can salvage the lives of many
more patients than you could before any hypertensive drug therapy, and that in
the mild and moderate grades of hypertension, there is a great deal of circum-
stantial evidence to indicate that reduction of blood pressure should prolong


76                MOLECULAR MODIFICATION IN DRUG DESIGN

lives by decelerating, or slowing down, the process of degenerative vascular
diseases. There is a lot of evidence to indicate that elevation of blood pressure
is bad for blood vessels, accelerates atherosclerosis and arteriosclerosis, and pro-
motes hypertrophy of the heart, and other bad things.

  That being the case, one would expect reduction of blood pressure to be
beneficial. It has been shown in experimental animals that animal atherosclero-
sis can go on at the same rate as in a normotensive animal if you make the ani-
mal hypertensive but keep his blood pressure from going up by giving him anti-
hypertensive agents.

  In man it is difficult to run a controlled trial. It takes many years to deter-
mine whether or not a patient with mild or moderate hypertension is going to
develop organic complications.  The only kind of studies we have are sort of
hindsight studies which are not very valid, but even these suggest that in mild
and moderate hypertension, life is prolonged by adequate blood pressure con-
trol.

  Dr. Page: As Dr. Freis suggested, this is our life blood. It has got to
work. The evidence to me is incontrovertible. The first bit that was men-
tioned by Dr. Freis, the reversal of malignant hypertension, has no question
about it; nobody would question it today.

  Believe me, in the first days, there was a pretty dismal group to take care
of.  All you could do was give better nursing, because the outlook was uni-
versally fatal.

  The second thing to realize is that it is not the height of the blood pressure
that really kills the individual. It is the effect of blood pressure and other
factors on the smooth muscles of the body. If you plot any measurement which
measures the change in the quality of smooth muscle, you will find that anti-
hypertensive drugs do make the curve of deterioration level out.

  The third thing-one that Dr. Freis did not mention-is that when there is
heart failure, very often antihypertensive reduction of blood pressure will over-
come the heart failure without even the use of digitalis.

  So if you put all these things together, we need not really go into computer
medicine or large scale statistics to prove what clinical experience and physi-
ological thinking will show you really happens.

  I would like to add just one more piece of advice-that I think the pharma-
ceutical industry and the chemists have perhaps restricted their thinking a
little too much in the kinds of drugs that they have worked with, as Dr. Freis
suggested. Perhaps they overdid the saluretic drugs and have not given enough
attention to the many other facets of the problem of blood pressure control
which are now apparent to anyone who works in the physiology and chemistry
of mechanisms which control blood pressure.

  Therefore you have got your work cut out for you, and you do not have to
keep beating some of the horses that are fairly well dead in order to accomplish
things. I would like to see another striking out anew and approaching some of
these other mechanisms which are just crying to be antagonized or to be used in
order to lower blood pressure.
  Dr. Cavallito:  In essence it is evident that the work of the past ten
or fifteen years has not been in vain. However, it is also evident that you still
have some unresolved problems.