Hypertension 1996 : One Medicine, Two Cultures
Angiotensin-II inhibitors: New perspectives
Francesco Colace
Cardiology Department, S. Eugenio Hospital, Rome
Although international guidelines for
the treatment of arterial hypertension agree on the demonstrated ability
to positively influence cardiovascular mortality and morbidity, they disagree
on the choice of hypotensive drugs to be administered at a first stage.
Indeed, the American JNC (Joint National Committee) recommends to employ
diuretics and Beta-blockers, since they are the only ones supported by favourable
studies, while the WHO and the ISH, to which the Italian Society for Arterial
Hypertension has conformed, allows physicians to choose freely among ACE-inhibitors,
calcium-antagonists, (11-antagonists, and other sympathetic system modulators.
Such disagreement should not be a surprise, since the so-called “ideal hypotensive
drug” does not exist: thus alternative drugs should not reasonably be excluded
if they have drawn the clinical community's attention due to their efficacy
and tolerability.
It is therefore easy to understand that, besides volume depletes (diuretics)
and sympatheticomimetic-amine antagonists (Beta-blockers, Alpha-blockers),
vasodilators, Ca++-channel blockers, K+-channel activators, and converting-enzyme
inhibitors (ACE-I) were largely used too.
The latter combine high effectiveness and tolerability with the merit of
contributing to the knowledge of several aspects of the renin-angiotensin
system (RAS) which, as we know, plays a crucial role in the pathogenesis
of arterial hypertension, of cardiac decompensation of heart hypertrophy
development and, probably, in the onset and development of atheromatous
plaques too.
One drawback of this drug group is the lack of a specific substrate for
the converting enzyme a kininase II (hydrolase): this enzyme, in fact, besides
promoting the transformation from ANG-l to ANG-II, also participates to
the inactivation of bradykinins and enkephalins, as well as of other biologically
active peptides, thus giving place to possible undesired side effects, such
as dry cough and angioedema. Moreover, as highlighted by recent research,
ANG-II production is not only due to the converting enzyme: other enzyme
activities, such as chymase, may produce ANG-II independently.
These comments clearly show that the most reasonable way to overcome such
limits is provided by a downstream RAS block, i.e. at receptor level.
This is no recent concept: about 20 years ago, saralasin, a peptide similar
to ANG-II, was demonstrated to interfere with the latter by inhibiting its
action through a receptor-blocking mechanism: the peptide could not be clinically
used, because it was ineffective per os, its half-life was too short and
it exerted a somewhat agonist action.
A few years went by during which this research was not further developed
until, during the 1980's a few simple non-peptidic imidazole derivatives
were discovered, such as S-8307 and S-8308, indeed not very active due to
a rather weak bind: these opened up the way to further research which, combined
with an improved knowledge of ANG-II receptors, led to the synthesis of
new preparations characterized by increased power, receptor affinity, and
bioavailability.
The introduction of an acid carboxyl function into the new molecules allowed
the oral intake of the same: the result was the synthesis of DUP-753 or
Losartan, in which the carboxyl group is replaced with a tetrazolic equivalent,
thus achieving good bioavailability and a long-term action.
Besides Losartan, other non-peptidic ANG-II antagonists were synthesized:
valsartan, candersartan, irbersartan, eprosartan. GR-138950, DP-123177,
CGP-421l2A. The last two agents, chemically similar to the others, showed
thoroughly different blocking effects, thus significantly contributing to
the discovery of the heterogeneous character of ANG-II receptors. In fact,
enough scientific data are available to assume the existence of at least
two types of receptors: the AT1 type, in which the block inhibits most of
the known effects of ANG-II, and the AT2 type, still to be explained, which
is found in huge quantities in foetal tissues and in non-mature brains,
as well as in adrenal glands, brain, mesometrium, and ovary follicles in
adults, and is very likely to be involved in growth and tissue/organ development
processes.
The problem of ANG-II receptors is very interesting and topical. Thus, before
describing the pharmacological and clinical properties of antagonists, it
should be reminded that two types of receptors are involved in the development
and regulation of the cardiovascular system: cytosol receptors (not bound
to the membrane) and membrane receptors.
The formers bind with and are activated by factors able to pass through
the plasma membrane, such as steroids, thyroid hormones and nitric oxide;
the latter are proteins that spread over the membrane and are necessary
both for the transportation of large molecules, e.g. lipoproteins, and for
the transmission of information through the membrane, by circulating hormones
or neurotransmitters.
Membrane receptors may be broken down into different groups based on their
structure and action mechanism. They primarily include: receptors coupled
with G proteins (activating GTP-binding proteins), tyrosine-kinase receptors,
adenyl-cyclase receptors, and receptors involved in receptor-mediated endocytosis.
G-protein coupled receptors constitute the largest membrane receptor group,
including the receptors for angiotensin, epinephrine and norepinephrine,
acetylcholine, adenosine, dopamine, endothelin, vasopressin, serotonin,
and many other hormones and neurotransmitters.
Receptor activation follows similar mechanisms for the different G-protein
coupled receptors, involving the activation of adenyl-cyclase. phosphatase
and kinase, as well as changes in intra-cellular calcium.
Several ANG-II antagonists were synthesized: most of them are still being
tested in animals and in man but, since Losartan is the most thoroughly
studied, according to current knowledge, we will refer to this drug in our
description of pharmacological and clinical properties.
Potassium Losartan is a non-peptidic, fully water-soluble imidazole derivative,
which causes the quick build-up of an active metabolite (E-3174or EXP-3174);
along with the latter, which is however much more powerful than the former,
it blocks AT1 receptors of ANG-II in many tissues, such as in smooth vascular
muscles, in adrenal glands, in kidneys, and in the heart, while inhibiting
all physiological activities of ANG-II. The subsequent suppression of the
negative feedback mechanism of ANG-II involves an increased renin activity
of plasma along with increased ANG-II plasma levels. In spite of this, the
anti-hypertensive effect of the drug and the reduction of aldosteronaemia
are ensured. Moreover no rebound is observed if the treatment is discontinued.
Losartan showed its blocking activity both for ANG-II and for ANG-I without
interfering with the metabolism of bradykinins or other biologically active
peptides. This specific action is responsible for the absence of side effects,
such as dry cough and angioedema.
Losartan and its active metabolite reach mean blood concentration peaks
after I hour and 3-4 hours respectively, since their half-life amounts to
2 hours and 6-9 hours respectively. Thus a long-term action is ensured,
and one daily dose is effective.
Elimination occurs both through the bile and the urine. Losartan does not
pass through the blood-brain barrier. Neither the original drug nor its
metabolite may be removed by haemodialysis.
Losartan's hypotensive effect is similar to enalapril (20 mg), to atenolol
(50-100 mg), and to slow-release felodipine (5-10 mg). Like enalapril, it
has no clinically significant effects on heart rate.
In patients with left ventricular impairment, Losartan exerted a positive
haemodynamic and neuro-hormonal effect: increased heart index, decreased
lung capillary pressure, peripheral vascular resistance, mean systemic arterial
pressure and heart rate, reduced plasma levels of aldosterone and noradrenalin.
In non-diabetic hypertensive patients with proteinuria, Losartan reduces
the latter and the fraction of albumine subject to urinary excretion. The
drug reduces the glomerular filtration fraction and preserves the latter's
speed. A fall in uric acid levels in serum is generally observed during
chronic treatment too; such effect may be positively considered in gout
patients.
Toxicity, carcinogenicity and mutagenicity studies carried out on this drug
did not highlight any harmful effects.
The drug has not been appropriately tested in children, therefore prescription
in this age group is not recommended. In addition, since renal perfusion
in the foetus depending on RAS development starts in the second term of
pregnancy, intake of this drug by pregnant women during the 2nd and 3rd
terms may be dangerous.
The mild hyperpotassaemia occasionally observed in treated patients never
called for the discontinuation of the Losartan treatment. The infrequent
SGVF increases subsided upon discontinuation of treatment. A possible liver
damage calls for a dose reduction. In hypovolaemic patients, following up,
for example, severe diuretic treatments, the drug should be administered
after restoring hydric conditions.
The primary indication for the clinical use of Losartan is represented by
arterial hypertension: several experimental and clinical studies, however,
also recommend use in case of chronic cardiac decompensation, in view of
a regression of ventricular hypertrophy and for post-infarct ventricular
restoration.
The clinical use of ANG-II antagonists, already under way, along with the
acquisition of new information on RAS physiology and physiopathology, particularly
with respect to the problems involved by its receptors, point out to a possible
wide clinical application of this new drug group in the near future.
Bibliography
- Dzau V.J,Pratt R.E. Structure, function and Pharmacology of Angiotensin II receptors. Receptors in Cardiovascular Disease. Copyright Merck Co., Inc., Whitehouse Station, N.J. U.S.A., 1994.
- Eberhardt R.T., Kevak R.M., Kang P.M. et all: Angiotensin II receptor blockade; an innovative approach to cardiovascular pharmacotherapy. J.Clin>Pharmacol. l993; 33:1023-38.
- Goldberg M.R., Bradstreet T.E., Mcwillians E.J. et all: Biochemical effects of losartan, a non-peptide angiotensin II receptor antagonist, on the renin-angiotensin-aldosterone system in hypertensive patients. Hypertension 1995; 25: 37-46.
- Dzau V.J., Mukoyama M. and Pratt R.E.: Molecular biology of angiotensin receptors: target for drug research? Journal of Hypertension 1994; 12 (suppl. 2) :S1-S5.
- Ardaillou R. and Chansel D.: Glomerular effects of angiotensin II: a reappraisal based on studies with non-peptide receptor antagonists. Journal of Hypertension 1993, 11 (suppl. 3): S43-S47.
- Timmermans P.B., Smith R.D.: A new class of therapeutic agents: the angiotensin II receptor antagonists. Cardiologia 1994; 39(suppl 1 al n 12): 397-400.
- Ambrosioni E., Bacchelli S.: Farmacologia clinica degli antagonisti dell' angiotensina II.
- Salvetti A., Virdis A.: Esperienza clinica con gli antagonisti dell' angiotensina II nell’ipertensione arteriosa. Cardiologia 1994; 39 (Suppl 1 al n 12): 405-408.
Edited by Aldo Campana,