The Hypotensive Activity and Side Effects

of Methyldopa, Clonidine, and Guanfacine

PlIiTER A. VAN ZwiETEN, MARTIN J. M. C. Tl-IOOLEN, AND

PlETER B. M. W. M. TlMMERMANS

SUMMARY Clonidine (Catapres, Catapresan), guanfacine (Estulic), and methyldopa (Aldomet)

are the prototypes of centrally acting antihypertensive drugs. Clonidine and guanfacine are lipophilic
drugs that readily penetrate into the brain, where they stimulate a-adrenergic receptors in the
pontomedullary region. The stimulation of these central a-adrenergic receptors has been shown to
activate an inhibiting neuron, which causes a reduction of peripheral sympathetic tone and a subse-
quent fall in arterial blood pressure and heart rate. Both a centrally initiated reduction of vagus reflex
activity and the activation of presynaptic os-adrenergic blocking agents in the heart may contribute to
the bradycardia. Studies indicate that methyldopa also penetrates into the brain, where it is converted
into a-methylnorepinephrine. This amine may stimulate the same central a-adrenergic receptors as
those activated by clonidine, which will result in a hypotensive effect. Possibly, a-methyldopamine
might also play a role. Accordingly, the modes of action of clonidine and a-methyldopa probably are
very similar at a basic level. The central adrenergic receptors probably are located postsynaptically.
Their receptor demand corresponds more closely to that of the a2-subtype. Central a,-adrenergic
receptors might possibly play a part in the modulation of vagally induced baroreflex bradycardia. A
discussion on the pharmacological basis of the side effects of the centrally acting antihypertensives has
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been limited to those adverse reactions that are somehow related to a-adrenergic receptors. Sedation,
a common side effect, appears to be mediated by central a2-adrenergic receptors, at least in animal
models. The withdrawal syndrome, observed on abrupt cessation of treatment with clonidine, appar-
ently also involves a-adrenergic receptors; however, why methyldopa does not precipitate a withdraw-
al phenomenon in the same animal model where clonidine was studied cannot be explained at present.
(Hypertension 6 (Suppl. II): 11-28-11-33, 1984)

KEY WORDS • methyldopa • central hypotensive activity clonidine

guanfacine • a-adrenergic receptors

T HE central nervous system, in particular struc-

tures in the brain stem, is known to play a
major part in the regulation of the peripheral
circulation. For this reason it can be supposed that
drugs could interfere with blood pressure regulation at
the level of the CNS. It has indeed been shown that
certain antihypertensive drugs owe their hypotensive
action primarily to an interference with receptors locat-
ed in the brain stem, the region of the CNS where
circulatory regulation predominantly is located.
Clonidine, guanfacine, and methyldopa are the pro-
totypes of centrally acting antihypertensive drugs,
which are known to act primarily via a-adrenergic
receptors in the brain. These drugs have found wide
From the Division of Pharmacolherapy. University of Amster-
dam. Plantage Muidergracht 24. 1018 TV Amsterdam. The Nether-
lands.
Address for reprints: P. A. van Zwieten. Division of Pharma-
cotherapy. University of Amsterdam. Plantage Muidergracht 24.
1018 TV Amsterdam. The Netherlands.
clinical application. In particular, methyldopa has
been used extensively for many years. Guanabenz,
tiamenidine, lofexidine, and azepexole are experimen-
tal compounds with a similar mode of action, but their
therapeutic values have not been established in detail.
Several compounds also have been developed that
decrease blood pressure via central mechanisms that
do not involve the central a-adrenergic receptors. Cho-
linergic, opioid, dopaminergic, serotoninergic, and
gamma-aminobutyric acid (GABA)-ergic compounds
with central hypotensive activity have been developed.
None of these latter compounds, however, have yet
proved of therapeutic value, and the introduction of
these types of drugs in the treatment of arterial hyper-
tension does not seem to be imminent. For this reason
the present survey shall remain limited to the mode of
action and applications of clonidine, guanfacine, and
methyldopa, with an emphasis on the characteristics of
the central a-adrenergic receptors involved in the me-
diation of the central hypotensive action of these
drugs.

11-28
 CENTRALLY ACTING ANTIHYPERTENSIVES/ra// Zwieten et al.
CH3
HO CH2-C-NH2 • * H O - ^ CH2-C-NH2
I decarboxylase
COOH
OH OH
-methyl-DOPA L-<x- methyl-dopamine
FIGURE 1. Biotransformation of methxldopa into a-melhyldopainine, which in turn is converted to a-methvlnorepinephrine. a-
Methvlnorepinephrine generally is assumed to be the active metabolite that stimulates central a2-adrenergic receptors and therefore
reduces peripheral sympathetic tone and arterial blood pressure. (See text for details.)
The discovery of the centrally acting antihyperten-
sive drugs, which act on the central a-adrenergic re-
ceptors, has given strong impetus to the study of the
central regulation of peripheral blood pressure. This
impetus, of particular value in fundamental physiol-
ogy, pharmacology, and pathophysiology, may be as
important as the therapeutic application of the centrally
acting drvgs in hypertensive disease.
Centrally Acting Antihypertensive Agents
Compounds Interacting with a-Adrenergic Receptors
Reserpine is the oldest antihypertensive drug that
owes at least part of its antihypertensive potency to a
central mechanism.1 It should be realized that the ma-
jor mechanism contributing to the drug's hypotensive
potency is the depletion of norepinephrine from pe-
ripheral storage sites in postganglionic sympathetic
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nerve endings. The central mechanism of reserpine
probably involves the stimulation of central a-adrener-
gic receptors by endogenous norepinephrine released
from presynaptic storage sites.
A centrally acting drug that has been (and still
is) widely used, is the amino acid methyldopa. In
fact, this compound should be considered a prodrug,
which can only act after its biotransformation to the
active degradation product a-methylnorepinephrine
(Figure 1). The latter compound is likely to be the
active agent that interacts with the central a-adrenergic
receptors,2"4 although others have suggested that a-
methyldopamine is also a metabolite with hypotensive
potency.5
A major group of centrally acting antihypertensives
that has been investigated thoroughly are the imidazo-
lidines and related compounds, of which clonidine and
guanfacine are clinically relevant prototypes. The
structure-activity relationship for imidazolidines has
been studied in a quantitative manner. The subject has
been reviewed in full detail by Timmermans et al >7 In
spite of all the efforts to obtain a more active molecule,
clonidine remains one of the most potent agents in this
series. 67 Chemical alteration of the structure of the
phenyl moiety in the molecule or of the heterocyclic
nucleus rarely has led to compounds with higher activ-
ity than that of clonidine.
The results of the quantitative structure-activity
(QSAR) studies6 suggest that the hypotensive activity
of the molecule is governed by distinct steric and elec-
tronic characteristics. Moreover, lipophilicity also
11-29
OH CH3
hydxouylase
OH
L-o<-methyl-noradrenaline
seems to play an important part. From these studies has
emerged a hypothetical working model that visualizes
the mode of interaction between clonidine-like imida-
zolidines and the central receptor, which is the initial
target of the imidazolidine hypertensives.6 7
Recently, a chemical structure quite different from
the imidazolidines and related compounds has been
acknowledged to display central hypotensive activity,
mediated by central a-adrenergic receptors. Azepex-
ole (BHT 933) and BHT 920 are azepine structures
(Figure 2) that display a mode of action very similar to
that of clonidine and quanfacine.8 9
Studies on structure-activity relationships in central-
ly acting antihypertensive drugs have been limited to
clonidine and related imidazolines. Methyldopa (a-
methylnorepinephrine), although acting via a similar
mechanism that involves central a-adrenergic recep-
tors, is virtually the only active compound in its own
particular chemical series so that no meaningful study
on structure-activity relationships can be performed.10
Mode of Action Involving Central a-Adrenergic
Receptors
The concept that the central a-adrenergic receptors
are the initial target of clonidine and related centrally
acting antihypertensive drugs was formulated by
Schmitt in 1971."
Although methyldopa has been used against hyper-
tension for many years, only recently has its mode of
action as a centrally acting antihypertensive drug been
recognized —l2~15 after initial hypotheses (e.g., inhibi-
tion of dopa-decarboxylase, false transmitter theory)
had proved erroneous. The role of central a-adrenergic
receptors in the hypotensive action of guanfacine also
has been recognized recently.16"17
According to Schmitt's classical hypothesis, cloni-
dine is an agonist of central a-adrenergic recep-
t o r s . " 1 8 1 9 The stimulation of these receptors de-
creases peripheral sympathetic outflow, which causes
a fall in blood pressure. The a-adrenergic receptors act
as antagonists toward the same receptors. The reduc-
tion in peripheral sympathetic tone by clonidine and
related drugs has been demonstrated experimentally as
a diminished frequency and intensity in discharges of
the splanchnic nerve: plasma catecholamines and plas-
ma renin activity simultaneously are reduced.20"21 (For
reviews see 11, 18 and 19.)
Guanfacine has been shown to display the same
mode of action as clonidine with respect to its antihy-
Downloaded from http://ahajournals.org by on September 25, 2020
 CENTRALLY ACTING ANTIHYPERTENSIVES/va/i Zwieten et al.
Excitation of the central a-adrenergic receptors is
assumed toenhance the activity of an inhibitory neuron
and will therefore depress peripheral sympathetic tone.
The reduced sympathetic tone satisfactorily explains
the fall in blood pressure caused by clonidine, guanfa-
cine, and methyldopa.
By means of a careful pharmacological analysis
with specific a,- and a,-adrenergic receptor antago-
nists we have been able to demonstrate that the central
hypotensive effect was readily antagonized by the se-
lective a2-adrenergic receptors rauwolscine and yo-
himbine, whereas corynanthine, a selective a,-adren-
ergic receptor, was much less effective24 (Figure 3).
Corynanthine is a diastereoisomer of rauwolscine and
for this reason possesses physicochemical properties
very similar to that of rauwolscine, but its receptor
affinity is selective for the a,-adrenergic receptors. 2526
Similar experiments with several centrally acting a-
adrenergic receptor agonists by Kobinger et al.19-27
have also indicated that the centrally acting a-adrener-
gic receptor involved in the hypotensive effect of drugs
resembles more closely the a 2 -subtype than the ar
subtype. Moreover, compound St 587, a lipophilic,
highly selective a,-adrenergic receptor agonist when
administered to the brain stem, on infusion into the
vertebral artery did not induce a hypotensive effect.28
Recent correlation calculations for various agonists
and antagonists 2729 - x also point toward the involve-
ment of a2-adrenergic receptors at the central level.
This view was challenged by some very recent stud-
Downloaded from http://ahajournals.org by on September 25, 2020
ies,31"34 which suggest that the character of the central
a-adrenergic receptors may not be completely com-
patible with either the a 2 - or the a,-subtype. Further
confirmation of these views is needed.
A certain inhibitory role of central a,-adrenergic
receptors recently has been proposed in the central
modulation of the baroreceptor-refiex vagal bradycar-
dia.35
rauwolscine •yohimbine
0.3 1 3 10 3 6 10
iii
10-
T*
T * T scine, yohimbine, and corynanthine and
20- IT
30-
T T
i.0-1
T mean arterial pressure (means ± SEM.N
C l o n i d i n e M^ig/kg, v.a.) i n d u c e d
maximal decrease in mean arterial p r e s s u r e (%)
11-31
In conclusion it seems justified to state that the a-
adrenergic receptors in the brain stem that mediate the
central hypotensive action of clonidine probably are
located at postsynaptic sites; their receptor demand
appears to be that of the a2-adrenergic receptor sub-
type. The central a-adrenergic receptors that facilitate
the vagally mediated bradycardia most likely are also
of the a,-type; however, an inhibitory role of central
a,-adrenergic receptors on vagal reflex bradycardia
has been suggested.35
Side Effects: Pharmacological Basis
The discussion of the role of central a-adrenergic-
receptor-involved side effects shall be limited to the
prototypes of the centrally acting hypotensive drugs:
clonidine, guanfacine, and methyldopa.
It has been shown in animal experiments that seda-
tion, a very common adverse reaction to centrally act-
ing antihypertensives, involves the stimulation of cen-
tral a-adrenergic receptors that are probably of the a 2 -
subtype24•36; however, the pharmacological methods
currently available do not allow a definite decision
whether these a,-adrenergic receptors are located at
either pre- or postsynaptic sites. At least on theoretical
grounds it would seem very difficult to develop new
centrally acting antihypertensive drugs that do not dis-
play a substantial degree of sedation as an adverse
reaction because both the central hypotensive and the
sedative effects apparently are mediated by identical
(or at least very similar) receptors of the a 2 -subtype.
Studies have demonstrated that clonidine-induced
bradycardia is caused by a complex combination of the
following three phenomena: (1) the centrally induced
reduction of peripheral sympathetic tone, which in-
volves central a2-adrenergic receptors" 1 8 1 9 ; (2) the
enhancement of vagal reflex bradycardia initiated at
the level of central a2-adrenergic receptors36; (3) the
stimulation of presynaptic a2-adrenergic receptors in
+corynanthine lug/kg, v.a.)
10 30 100
:::: *
FIGURE 3. Interaction between rauwol-
hr
If
the central hypotensive effect of cloni-
dine in chloralose-anesthetized cats.
Clonidine (I ixglkg) was infused into the
left vertebral artery 15 minutes after ei-
ther saline (control, black column) or
the antagonist. Columns represent
maximal hypotensive effect of clonidine
calculated as percentage decrease in
= 5-7). * = p < 0.05 (Student's t-test)
with respect to nontreated control group
(from Timmermans el al.24; reprinted by
permission).
 11-32 HYPERTENSION SUPPLII V O L 6 ,
the heart, which causes an impaired release of norepi-
nephrine.37
The dry mouth caused by clonidine and related
drugs also has been shown to involve a-adrenergic
receptors: the excitation of presynaptic a,-adrenergic
receptors on peripheral parasympathetic neurons
causes reduced salivary flow.38
It seems likely that the corresponding and very simi-
lar side effects of guanfacine and methyldopa are
caused by the same mechanisms that clonidine in-
duces; however, these drugs have not been studied as
systematically.
Withdrawal Phenomena
It has been reported several times that the rapid
interruption of antihypertensive therapy with clonidine
causes withdrawal phenomena, which are character-
ized by various symptoms that reflect sympathetic hy-
peractivity. The clinical aspects have been discussed
by Reid39 and Hannson.40 Recently we have been able
to develop an animal model that is suitable to demon-
strate and study the withdrawal phenomena of central-
ly acting and other antihypertensives.41
Both clinical and animal model studies discussed in
this article have suggested the following differences
with respect to the three prototypes of the centrally
acting antihypertensive drugs: (1) Clonidine may
cause withdrawal phenomena characterized by hyper-
activity of the sympathetic nervous system, on sudden
cessation of antihypertensive therapy with this drug; as
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a rule, a genuine blood pressure overshoot does not
occur. (2) Guanfacine has been found to cause with-
drawal phenomena but to a very modest and clinically
irrelevant degree. The limited extent of the guanfacine
withdrawal syndrome in humans and rats most likely is
caused by the lower elimination rate compared with
clonidine.4I"13 (3) Methyldopa has been reported to
cause withdrawal phenomena in humans only in ex-
ceptional cases; in animal experiments this drug has
not caused relevant withdrawal phenomena.41 M
Why methyldopa does not clearly cause withdrawal
phenomena cannot be explained at present. Neither are
we informed on the detailed mechanism of the with-
drawal phenomenon of clonidine. Central a-adrener-
gic receptors appear to be involved, as the adminis-
tration of yohimbine (an a 2 -adrenergic receptor
antagonist) but not that of prazosin (an a,-adrenergic
receptor antagonist) provoked strong withdrawal ta-
chycardia during a 12-day continuous infusion of ei-
ther clonidine or guanfacine.41-43 M Yohimbine inject-
ed during an infusion of methyldopa did not provoke
withdrawal tachycardia, which indicates that other
than pharmacokinetic factors may explain the virtual
absence of withdrawal phenomena after cessation of
treatment with methyldopa.43
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