Antihypotensives 1

Antihypotensives
Hans Dieter Lehmann, Knoll AG, Ludwigshafen, Federal Republic of Germany
Marco Thyes, Knoll AG, Ludwigshafen, Federal Republic of Germany

1. Introduction . . . . . . . . . . . . . . . . . 1 3.1. Ergot Alkaloids . . . . . . . . . . . . . . . 4

2. Sympathomimetics . . . . . . . . . . . . 1
3.2. Mineralocorticoids ............ 5
3. Substances Having Other Modes of
Action . . . . . . . . . . . . . . . . . . . . . 4 4. References . . . . . . . . . . . . . . . . . . 5

1. Introduction portant blood pressure increasing agents are de-

scribed in this article [1].
Blood pressure increasing agents are used to
counteract acute drop of blood pressure, such
as is observed in surgery, severe infectious dis-
eases, and shock. A further field of use is per-
2. Sympathomimetics
sistent hypotension caused by circulatory dys-
The physiological neurotransmitters of the
regulation when standing (postural hypoten-
sympathetic (adrenergic) nervous system, nor-
sion); this results in cerebral ischemia, which
epinephrine and epinephrine, and the other syn-
in turn produces clinical symptoms. Ortho-
thetic sympathomimetics stimulate the adren-
static dysregulation can also be induced by
ergic α- and/or β-receptors. The stimulation
drugs, in particular by blood pressure lower-
of α-receptors causes the smooth muscle cells
ing drugs (→ Antihypertensives), and by drugs
of resistance and capacitance vessels to con-
acting on the central nervous system (psy-
tract; the stimulation of β1 -receptors leads to
chotropic drugs). Hypotensive circulatory dis-
increased cardiac output, and the stimulation
orders may be volume-related or regulation-
of β2 -receptors causes vascular smooth mus-
related. In volume-related hypotension there is
cle cells to relax. Norepinephrine primarily ac-
an absolute deficit in blood volume, which must
tivates α-receptors, whereas epinephrine stimu-
be compensated for by infusing blood or plasma
lates both α- and β-receptors. Both neurotrans-
expanders (→ Blood). Regulation-related hy-
mitters are only suitable for intravenous injec-
potension originates either in the central ner-
tion, especially for continuous i.v. infusion, be-
vous system or in the periphery, involving ca-
cause of their low bioavailability (≈ 3 %) and
pacitance vessels (veins and venules) or resis-
short half-life (≈ 2 min) [2].
tance vessels (small arteries and arterioles) or
both. In regulation-induced hypotension there
is an absolute or relative deficiency in the re- Norepinephrine [51-41-2], (R)-(−)-4-(2-
lease of norepinephrine from nerve terminals of amino-1-hydroxyethyl)-1,2-benzenediol, (−)-
the sympathetic nervous system in the vascular norepinephrine, noradrenaline, (−)-noradrenal-
section. The release of norepinephrine is cru- ine, its hydrochloride [329-56-6], and its (R,R)-
cial to maintain vascular tone. Drug treatment, hydrogen tartrate [51-40-1] are described in
therefore, serves to supply vasoconstrictor sub- more detail under → Hormones, Chap. 2.2.
stances, either acting like norepinephrine, i.e.,
sympathomimetics, or having other modes of ac-
tion, i.e., ergot alkaloids, peptides, and mineralo-
corticoids. The mineralocorticoids also increase
total blood volume. In acute hypotensive crises
the drugs must be administered intravenously. Trade names(hydrochloride): Arterenol
For long-term hypotensive dysregulations orally (Hoechst Marion Roussel).
effective substances are needed. The most im-

c 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

10.1002/14356007.a04 229
2 Antihypotensives
R,R-Hydrogen tartrate: Levophed (Ab-
bott, Breon), Levophed Bitartrate (Sanofi
Winthrop), Levophed special (Abbott), Nora-
drenalin 1 : 1000 JENA-PHARM (Jenapharm),
Noradrenalina tartrato (Monico, Salf, Sifra).
Epinephrine [51-43-4], (R)-(−)-4-[1-
hydroxy-2-(methylamino)ethyl]-1,2-benzene-
diol, (−)-epinephrine, adrenaline, (−)-adrenal-
ine, its hydrochloride [55-31-2] and its hydrogen
tartrate [51-42-3] are described in more detail
under → Hormones, Chap. 2.2.
Trade names: Adrenalina ISM 1 : 1000
(Nuovo ISM), Anahelp (Stallergènes), Anakit
(Dome-Hollister-Stier), Dyspne-Inhal (Augot),
EPIFRIN (Allergan), EpiPen (Dey), Primatene
(Whitehall-Robins), Sus-Phrine (Forest).
Hydrochloride: Adrenalin 1 : 10000 (B.
BRAUN), Ana-Kit (Bayer Allergy), Anaphy-
laxie-Besteck (Bencard), Fastjekt (Allergo-
pharma), Infectokrupp Inhal (Infectopharm),
Suprarenin (Hoechst Marion Roussel).
Hydrogen tartrate: Adrenalin 1 : 1000 JENA-
PHARM (Jenapharm).
Dopamine [51-61-6], 4-(2-aminoethyl)-1,2-
benzenediol, 3-hydroxytyramine, C8 H11 NO2 ,
M r 153.18, is very sensitive to oxygen; its hydro-
chloride [62-31-7] melts at 247 ◦ C.
Dopamine is the direct endogenous precur-
sor of norepinephrine. Its cardiovascular ef-
fects are different from those of norepinephrine
and epinephrine. It dilates coronary, cerebral,
renal, and mesenteric arteries by interacting
with dopaminergic receptors. It also activates
adrenergic α- and β-receptors, which in turn
causes capacitance vessels to constrict and car-
diac output to increase. With this combined ef-
fect dopamine is well suited for shock treatment:
it increases blood pressure, and at the same time
renal and mesenteric blood flow is augmented.
In terms of pharmacokinetics, dopamine is sim-
ilar to norepinephrine and epinephrine and must
be administered by continuous intravenous in-
fusion [3].
Dopamine is synthesized from veratrole by
chloromethylation to form veratryl chloride, fol-
lowed by cyanation, catalytic hydrogenation,
and demethylation.
For further methods of synthesis, see [9].
(see a: [4]; b: [5]; c: [6]; d: [7]; e: [8])
Trade names(hydrochloride): Dopamin Frese-
nius (Fresenius-Klinik), Dopamin-ratiopharm
(ratiopharm), Dopamin Solvay (Solvay
Arzneimittel), Dopamine Pierre Fabre (Pierre
Fabre Cardio Vasculaire), Dopamine Lucien
(Therabel Lucien Pharma), Dopamine Nativelle
(Procter & Gamble), Revivan (Astra).
Norfenefrine [536-21-0], α-(aminometh-
yl)-3-hydroxybenzenemethanol, C8 H11 NO2 ,
M r 153.18, is closely related to norepinephrine;
its hydrochloride [4779-94-6] melts at
159 – 160 ◦ C.
The bioavailability of norfenefrine is only
slightly greater (≈ 5 %) than that of nor-
epinephrine because the major portion is metab-
olized in the intestinal wall and the liver (exten-
sive first-pass effect). When administered orally
the compound is only effective at high dose lev-
els [10].

Norfenefrine can be synthesized from m-
hydroxyacetophenone as shown in the following
scheme [11]:
Norfenefrine is also obtained from m-
hydroxyacetophenone by nitrosation to form m-
hydroxy-(hydroxyimino)acetophenone and sub-
sequent catalytic hydrogenation [12]:
For a further method of synthesis, see [13].
Trade names(hydrochloride): Coritat (Green
Cross), Energona (Maurer), Norfenefrin “Zi-
ethen” (Ziethen), Norfenefrin retard forte-
ratiopharm (ratiopharm), Novadral (Goedecke),
Zondel (Grelan).
Midodrine [42794-76-3], 2-amino-N-[2-
(2,5-dimethoxyphenyl)-2-hydroxyethyl]acet-
amide, C12 H18 N2 O4 , M r 254.28, and its hydro-
chloride [3092-17-9], mp 202 – 204 ◦ C, act on
resistance and capacitance vessels by stimulat-
ing α-receptors. Midodrine is a prodrug from
Antihypotensives 3
which the active major metabolite ST 1059,
α-(aminomethyl)-2,5-dimethoxybenzenemeth-
anol, is released by enzymatic cleavage of
glycine. According to animal experiments the
enteral efficacy of midodrine is better than that
of the sympathomimetics already described.
However, no data on the bioavailability and
half-life of this relatively new compound have
been published [14]. Synthesis [15]:
For further routes to midodrine, see [16].
Trade names(hydrochloride): Gutron (Guidotti,
Nycomed), Metligine (Taisho), ProAmatine
(Roberts).
Etilefrine [709-55-7], α-[(ethylamino)me-
thyl]-3-hydroxybenzenemethanol, C10 H15 NO2 ,
M r 181.23, mp 147 – 148 ◦ C, and its hydro-
chloride [943-17-9], mp 121 ◦ C, act both on
α-receptors and on β-receptors. This not only
increases the tone of resistance and capacitance
vessels but also improves the cardiac output. The
bioavailability of the compound is 55 % when
administered in aqueous solution, 35 % when
administered as an instant-release tablet, and
17 % as a slow-release tablet. Bioavailability
increases to 61 % when 2 mg of dihydroergot-
amine (see page 4) is added to a slow-release
tablet [17].
4 Antihypotensives
Etilefrine can be synthesized using m-acet-
oxy-ω-bromoacetophenone as the starting ma-
terial:
(see a: [18]; b: [19]; c: [20], [21])
For an alternate route to etilefrine, see [20].
Trade names(hydrochloride): Adrenam (NAM
Neukönigsförder), Bioflutin-N (Südmedica),
Cardanat (Temmler Pharma), Cardialgine (MIP
Pharma), Circupon RR (gegepharm), Circuvit E
(Pharma Wernigerode), Confidol (Medopharm),
Effortil (Boehringer Ingelheim), etil 5 von ct (ct-
Arzneimittel), ETI-PUREN (Isis-Puren), Kreis-
lauf Katovit (Boehringer Ingelheim), Thomasin
(Apogepha).
Hydrochloride in combination with dihydro-
ergotamine methanesulfonate see page 4.
Ameziniummetilsulfate [30578-37-1],
4-amino-6-methoxy-1-phenylpyridazinium
methyl sulfate, amezinium, C12 H15 N3 O5 S,
M r 313.33, mp 176 ◦ C (decomp.), also acts
via adrenergic α- and β-receptors. Its chem-
ical structure differs from that of other sym-
pathomimetics. At the adrenergic neurons
the drug causes specific, reversible inhibi-
tion of monoamine oxidase, inhibition of nor-
epinephrine re-uptake, and a slight increase in
norepinephrine release. Therefore, the agent is
only effective in vessels innervated by adren-
ergic nerves, thereby enhancing sympathetic
activity. Unlike other indirectly acting sympa-
thomimetic drugs, ameziniummetilsulfate does
not deplete the norepinephrine stores in sympa-
thetic nerve terminals. Its bioavailability is ca.
60 %, the terminal half-life is 9 – 17 h [22].
The substance is prepared by first treat-
ing 4,5-dichloro-2-phenyl-3(2H)-pyridazinone
[23] with ammonia to give mainly 5-ami-
no-4-chloro-2-phenyl-3(2H)-pyridazinone and
some 4-amino-5-chloro-2-phenyl-3(2H)-pyrid-
azinone [23].
After removal of the 4-amino-5-chloro deriva-
tive by extraction with chloroform [24], [25], the
5-amino-4-chloro compound is dehalogenated
with hydrogen over Raney nickel [23], [25] or
with sodium borohydride in the presence of pal-
ladium on charcoal [26]. Subsequent reaction
with dimethyl sulfate leads to ameziniummetil-
sulfate [25], [27].
Trade names: Regulton (Knoll Deutschland),
Risumic (Dainippon), Supratonin (Grünenthal).
3. Substances Having Other Modes
of Action
3.1. Ergot Alkaloids
Dihydroergotamine [511-12-6], (5 α,10α)-
9,10-dihydro-12 -hydroxy-2 -methyl-5 -(phen-
ylmethyl)ergotaman-3 ,6 ,18-trione, 9,10-di-
hydroergotamine, is treated in more detail under
→ Alkaloids, Chap. 11.3.2.; the methanesulf-
onate [6190-39-2] melts at 230 – 235 ◦ C (de-
comp.).

Dihydroergotamine acts on adrenergic α-
receptors and serotonin receptors of capacitance
vessels and increases their tone. In this way
blood supply to the heart and stroke volume are
improved. As a consequence, blood pressure is
increased. To a great extent dihydroergotamine
acts selectively on capacitance vessels, whereas
an increase in the tone of resistance vessels has
only been demonstrated in denervated vessel
preparations. The bioavailability of the drug is
only about 1 %. However, its effect on venous
tone has been clearly demonstrated in animals
and humans after oral administration and can be
explained by an accumulation of the agent in
the smooth muscle cells of the vessels. There-
fore, its effect is largely independent of plasma
levels [28].
Dihydroergotamine can be obtained by hy-
drogenating ergotamine (→ Alkaloids) in the
presence of a palladium catalyst [29].
Trade names(methanesulfonate): Agit de-
pot sanol (Sanol), Angionorm (Farmasan),
clavigrenin (Hormosan), DET MS (FUISZ
PHARMA), D.H.E. 45 (Novartis), DHE-
PUREN (Isis-Puren), DHE-ratiopharm (ratio-
pharm), Dihydergot (Novartis Pharma), Di-
hytamin (Arzneimittelwerk Dresden, Temm-
ler Pharma), Diidergot (Sandoz), Ergomimet
(Klinge), Ergont (Desitin), ergotam von ct (ct-
Arzneimittel), Ikaran (Pierre Fabre, Formenti),
Migranal (Novartis), Seglor (Sanofi Winthrop,
Synthelabo), Verladyn (Verla).
Methanesulfonate in combination with etile-
frine hydrochloride: Effortil plus (Boehringer
Ingelheim), Ergolefrin (gegepharm), Agit plus
sanol (Sanol), Dihydergot plus (Novartis
Pharma), Ergomimet plus (Klinge).
3.2. Mineralocorticoids
Therapy of postural hypotension by miner-
alocorticoids (renin – angiotensin – aldosterone
Antihypotensives 5
mechanism) is based on sodium and water reten-
tion in the body. This increases the blood volume
and makes the vessels more sensitive to vaso-
constrictive agents, resulting in augmented tone
of resistance and capacitance vessels. Fludro-
cortisone is normally used; it has a bioavail-
ability of 100 %. On prolonged administration,
fludrocortisone inhibits the production of renin,
angiotensin, and aldosterone and causes atro-
phy of aldosterone-producing cells in the adrenal
gland. Therefore, fludrocortisone is only used in
the treatment of postural circulatory dysregula-
tion where other drugs have failed. In any case
treatment must be short [30].
Fludrocortisone [127-31-1], (11β)-9-
fluoro-11,17,21-trihydroxypregn-4-ene-3,20-
dione, 9α-fluorohydrocortisone, 9α-fluoro-
cortisol, C21 H29 FO5 , M r 380.46, mp
260 – 262 ◦ C (decomp.), [α]23 ◦
D + 139 (c = 0.55,
95 % ethanol); 21-acetate [514-36-3],
C23 H31 FO6 , M r 422.48, crystalline substance,
several polymorphic forms, mp 233 – 234 ◦ C
(occasionally melting at 205 – 208 ◦ C, resolidi-
fication and subsequent melting at 226 – 228 ◦ C,
[α]23 ◦
D + 123 (c = 0.64, chloroform); for the syn-
thesis of the 21-acetate, see [31–33] and for its
conversion to fludrocortisone, see [31], [34]; see
[35] for a broad description of the 21-acetate and
[36] for a process giving dense granular prisms
of the 21-acetate.
Trade names: Astonin H (Merck).
21-Acetate: Florinef (Bristol-Myers Squibb),
Florinef Acetate (Apothecon), Fludrocortison
(Bristol-Myers Squibb).
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Antihypotensives 7
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