administrarea corecta a antihipertensivelor in functie de farmacocinetica
TRANSCRIPT
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www.medscape.com
Authors and Disclosures
Stefano Taddei, Rosa Maria Bruno and Lorenzo Ghiadoni
Department of Internal Medicine, University of Pisa, Pisa, Italy
Correspondence
Prof. Stefano Taddei, Department of Internal Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy.
E-mail:[email protected]
FromAmerican Journal of Cardiovascular Drugs : Drugs, Devices,
and Other InterventionsThe Correct Administration of Antihypertensive Drugs
According to the Principles of Clinical PharmacologyStefano Taddei; Rosa Maria Bruno; Lorenzo Ghiadoni
Posted: 02/09/2011; Am J Cardiovasc Drugs. 2011;11(1):13-20. 2011 Adis Data Information BV
Abstract and Introduction
Abstract
Control of cardiovascular (CV) risk factors, particularly hypertension, is still unsatisfactory, resulting in
excess CV morbidity and mortality worldwide. CV risk is linearly associated with an increase in bloodpressure (BP) values, and clinical studies have clearly demonstrated that BP lowering represents the most
effective means of preventing CV events. However, while BP reduction is a fairly easy target, BP
normalization is much more difficult to achieve, and adequate BP control (
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1. Introduction
Despite the great value that we attribute to scientific literature and guidelines, very often the clinical reality is
far from what would be expected on the basis of shared knowledge. Atypical example is the effectiveness of
hypertension treatment in the general population. It is well established that cardiovascular (CV) diseases
represent the leading causes of morbidity and mortality worldwide, and that this is related to the high
prevalence of CV risk factors and the failure to control them adequately. [1,2] Essential hypertension is
considered the most important CV risk factor on the basis of its very high incidence (around 50% in the
adult population) and its direct, linear relationship with CV events. [3,4]
Treatment of hypertensive patients is based on blood pressure (BP) normalization, which represents the
main mechanism by which antihypertensive treatment reduces morbidity and mortality. [5] In line with this, the
2007 European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines on the
management of hypertension recommend a target BP within the range of 130139/8089mmHg in all
hypertensive patients.[6,7]
In this review, we discuss how clinical pharmacology can be used to achieve BP goals in patients with
hypertension.
PubMed searches were performed for English-language articles on the treatment of hypertension,
antihypertensive therapy, combination therapy in hypertension, and clinical pharmacology of
antihypertensive drugs, published from 2000 to the present. In particular, reviews, consensus
statements/guidelines, and meta-analyses relevant to the above-mentioned issues were included. Earlier
works, particularly those concerning the clinical pharmacology of antihypertensive drugs, were also
evaluated. As a limitation, it has to be noted that this is not a systematic and exhaustive review of the
published literature. This was beyond the purpose of this review, which was to merge the evidence from
clinical trials, pharmacology studies, and the recommendations of international guidelines, in order to
implement them in daily practice.
2. BP Normalization in the Community
One would expect that the availability of a relatively large number of classes of antihypertensive drugs
would make the reduction of BP an easily achievable target. However, reducing BP is not equivalent to
normalizing it, particularly in clinical practice. BP normalization (
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emerging epidemic of resistant hypertension requires the correction of lifestyle factors (e.g. high sodium
intake), the diagnosis and appropriate treatment of secondary causes of hypertension, and the use of
effective multidrug regimens.[13] It is therefore necessary for physicians to start considering BP normalization
as a difficult goal that cannot be achieved by a simplistic approach. Knowledge of some basic principles of
clinical pharmacology can be a useful tool to reach this aim.
3. The Dosing of Antihypertensive Drugs According to Guidelines
The 2007 ESH/ESC guidelines recommend starting antihypertensive treatment with drugs at low dosages
(figure 1).[6] Although this principle might be applicable to some agents, it should be noted that it cannot be
applied to all antihypertensive drug classes. Thus, one major problem that should be reconsidered in the
treatment of hypertensive patients is the utilization of drugs at the correct and most effective dosages. More
consideration should be given to the application of the basic principles of clinical pharmacology to achieve
good antihypertensive treatment efficacy.
Figure 1. Therapeutic strategies in hypertensive patients according to European Society of
Hypertension/European Society of Cardiology guidelines. It is evident that guidelines always suggest
starting treatment in hypertensive patients with drugs at low doses. For certain drug classes, namely
ACE inhibitors, this is not correct, because of their pharmacological characteristics. Adapted from
Mancia et al [6]. CV= cardiovascular.
When we prescribe a drug for the treatment of hypertensive patients we should have in mind the following
issues: (i) potency of the drug, i.e. the degree of BP reduction; (ii) the duration of action of the drug, i.e. the
need for homogeneous BP reduction over the dosing interval (possibly 24 hours); and (iii) the specific effect
on target organ damage or related clinical conditions.
A relevant problem arises from the fact that very often we choose drugs on the basis of the efficacy
demonstrated in clinical trials, but we administer dosages without a clear knowledge of the clinical
pharmacology of the specific products.
Pivotal studies such as CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study), [14] HOPE
(Heart Outcomes Prevention Evaluation)[15] and EUROPA (EURopean trial On reduction of cardiac events
with Perindopril in stable coronary Artery disease)[16]
have changed our clinical practice, indicating thatblockade of the renin-angiotensin-aldosterone system (RAAS) with an angiotensin-converting enzyme
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(ACE) inhibitor can improve the prognosis of patients with high CV risk, such as those with coronary heart
disease or heart failure. However, the clinical application of these scientific results has been very
disappointing, since the dosage regimen used in clinical practice is usually lower than that employed in
clinical studies or indicated by the pharmacological characteristics of the molecules. As an example, in
clinical trials enalapril is used at dosages of 2040 mg/day, [14] but in clinical practice it is common to see
hypertensive patients treated with dosages of 510 mg/day. In the HOPE and EUROPA studies, ramipriland perindopril were used at dosages of 8 and 10 mg/day, [15,16] which are not the most commonly used
dosages in clinical practice.
It is also necessary to observe that several commercial formulations are not rational in terms of clinical
pharmacology, and are commercialized for marketing purposes only. This is particularly true for fixed
combinations, as explained in section 5. This kind of practice can generate a great deal of confusion,
especially among general practitioners who do not have specific experience in CV pharmacology.
In other words, what is the right dosage for each drug? Is it correct to adjust the dosage according to BP
values? Should the choice of dosage bemade in the same way for different drug classes, for instance, for
ACE inhibitors or calcium channel antagonists?
As mentioned above, effective BP lowering must take into account two main principles: (i) the extent of BP
reduction (which is expressed by the potency of the drug); and (ii) the need to cover the 24-hour dosing
interval (which requires using either compounds with a prolonged half-life or extended-release formulations
for once-daily administration). While the physician is aware of the extent of BP reduction, usually there is no
assessment of the 24-hour effect, which is a big mistake. A prolonged duration of action and a balanced
effectiveness throughout the 24-hour period reduces large fluctuations between the 'peak' and the 'trough'
effects,[17] which is an important aspect to consider because 24-hour mean values and BP variability are
closely related to CV events.[18,19]
4. The Dose-response Curve of Antihypertensive Drugs
Antihypertensive drug classes can be divided into two groups according to the characteristics of their dose-
response curve. As discussed above, current guidelines suggest the initiation of a low-dose
antihypertensive treatment.[6] However, this strategy can be applied only to drugs that present a linear dose-
response curve, i.e. their BP-lowering effect is proportional to the dose used (figure 2a). The prescription of
these molecules, which include diuretics, -adrenoceptor antagonists (-blockers), 1-adrenoceptor
antagonists, and calcium channel antagonists,[2023] allows the dosage to be tailored to the clinical
characteristics of each patient.
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Figure 2. Dose-response curves of antihypertensive drugs. (a) Drugs characterized by a linear dose-
response curve in terms of BP-lowering effect and with a duration of action sufficient to cover 24
hours. Drugs with these pharmacological characteristics can be used at different doses according to
the potency needed. (b) Drugs characterized by a non-linear dose-response curve. Drugs with these
pharmacological characteristics are not properly used at different doses, because the degree of BP
reduction induced by the low dose is the same as that determined by the high dose. The differencebetween the doses is only in the duration of action. (c) Drug classes characterized by an incorrect
titration. If BP is only measured at the dosing interval (usually 24 hours) and not also at the peak time,
it is not possible to ascertain whether the different BP-lowering effects observed over 24 hours are
related to a different potency or a different duration of action.
In contrast, for drug classes characterized by a non-linear dose-response curve, dosages differ mainly in
terms of duration of action, rather than in BP-lowering effect (figure 2b). Typical examples of such drugs are
ACE inhibitors[24] and possibly some angiotensin II type 1 receptor antagonists (angiotensin receptor
blockers [ARBs]).[25] To better explain this concept, the extent of BP reduction produced by an ACE inhibitor
at a low dosage (e.g. enalapril at 5mg/day) at peak is the same as that produced by a high dosage (e.g. 20
mg/day).[24] The difference between the two dosages concerns the duration of action, which is several hours
with the 5mg/day dosage, but covers an entire day with the 20 mg/day dosage. [24]
In some cases, physicians may believe that a low dosage of ACE inhibitor is effective in a patient with mild
hypertension (for example, during summer). This is a big mistake, from a pharmacological and clinical point
of view, and it generally originates from the fact that usually the patient takes the drug in the morning and
BP is measured during the daytime, when the compound has maximal efficacy, while during the night BP
values increase again. This pharmacological approach to hypertension is not adequate, because BP
control, as previously discussed, should be homogeneous throughout the 24-hour period. If a full dosage of
an ACE inhibitor is not well tolerated because of an excessive BP reduction, patients should be investigated
to confirm they really are hypertensive and, if this is the case, the presence of a renal artery stenosis should
be ruled out.
Thus, it is necessary to stress the concept that antihypertensive treatment should be titrated not only
considering the extent of BP reduction but also to achieve a constant 24-hour duration of action. This is
particularly true for drugs with a non-linear dose-response curve and in the case of combination therapy.
These parameters can be obtained by 24-hour ambulatory BP monitoring, or, though less precisely, by
repeated (at peak and trough) home BP recordings. [17,19]
Why are ACE inhibitors on the market at low dosages? Low dosages were marketed for patients with heart
failure, usually having low BP values and receiving concomitant diuretic therapy. Thus, in these patients it is
crucial to check whether the administration of the ACE inhibitor is well tolerated, especially in terms of BP
reduction. The fact that these drugs do not have a linear dose-response curve makes the use of a low
dosage ideal for establishing the tolerability of the treatment.[17]
In fact, the BP reduction induced by a lowdosage is similar to that induced by a high dosage, but with a shorter duration, which can be useful in the
case of excessive hypotension. If the low dosage is well tolerated, it can be progressively increased to
reach the full dosage.
However, in clinical practice, even in patients with heart failure, ACE inhibitors are underused and
underdosed.[26] A contributing factor might be that the summary of product characteristics and the
prescribing information documents may sometimes be misleading in terms of dosage adjustments. For
instance, according to these documents, the initial dosage recommended in hypertensive patients not on
diuretics is 5mg/day for enalapril and 2.5 mg/day for ramipril and the maintenance dosages range between
10 and 40 mg/day for enalapril and 510 mg/day for ramipril, which suggests the drug dosage should be
adjusted according to the BP response.
[27,28]
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Utilization of an ACE inhibitor at a low dosage is a big clinical mistake, not only in terms of evidence-based
medicine, but also in terms of the pharmacological properties of these drugs. Moreover, the physician must
be very careful to avoid compounds or formulations of ACE inhibitors that do not ensure full coverage of the
24-hour effect.[29] The different ACE inhibitors can be classified according to their duration of action (table I).
Of course, compounds characterized by a short duration of action should be administered at least twice
daily, while compounds characterized by a long duration of action should always be administered at thestandard dosage (e.g. enalapril 20 mg/day).
Table I. Duration of action of ACE inhibitors
Short duration of action
Captopril, delapril, quinapril, spirapril
Dosing: two or three times daily
Long duration of action
Enalapril, benazepril, cilazapril, fosinopril, lisinopril, perindopril, ramipril,
trandolapril, zofenopril
Dosing: once daily
A different approach can be used with drugs characterized by a linear dose-response curve. These drugs
have a duration of action sufficient to cover 24 hours (because of a prolonged half-life or the availability of
slow-release formulations) and dosage increases are associated with a greater BP-lowering effect.[20,21,23]
Thus, a low dosage might be appropriate as a starting dosage for calcium channel antagonists (e.g.
amlodipine 5mg/day or lercanidipine 10mg/day) or diuretics (e.g. hydrochlorothiazide 12.5mg/day or
indapamide 0.625mg/day). The dosage can be increased progressively according to the extent of BP
control and, in principle, one might expect that the recommended dosages of these drugs can be exceeded
if BP reduction is still insufficient. Unfortunately, this approach is often not possible in clinical practice due to
an increase in the incidence of side effects (figure 3).[21,23]
Typical examples include ankle edema caused bycalcium channel antagonists, electrolyte alterations caused by diuretics, and orthostatic hypotension caused
by 1-adrenoceptor antagonists. For example, the dose-response relationship for hydrochlorothiazide is
linear between 3 and 25mg/day; higher dosages achieve only minor further BP reductions, while the
incidence of hypokalemia continues to increase.[21] In contrast, it is important to observe that the most
frequent side effect induced by ACE inhibitors, i.e. cough, is not dose dependent and, therefore, even
considering this issue, it is not rational to reduce the dosage to improve tolerability.
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Figure 3. Usually the shapes of drug dose-response curves are different for the BP-lowering effect
and incidence of side effects. At low doses, side effects are minimal while at high doses the incidence
of side effects dramatically increases (typical examples are the ankle edema caused by calcium
channel antagonists or the electrolyte alterations caused by diuretics).
Whether ARBs present a linear or non-linear dose-response curve has been debated for a long time. This
derives largely from a wrong interpretation and design of studies performed during drug development.
Indeed, regulatory agencies (e.g. the US FDA and the European Medicines Agency) usually request that
dose-finding studies with parallel design be conducted, i.e. using different doses in different patient groups,
for regulatory purposes. Results from dose-finding studies suggested that the dose-response curve for
some ARBs may be flat; however, it must be taken into account that BP values were measured at the
dosing interval (24 hours). Without a further measurement of BP at the peak time, it is not possible to
ascertain whether the different BP-lowering effects observed during the 24-hour period are related to a
different potency or to a different duration of action (figure 2c). Conversely, dose-titration studies within the
same patient groups and studies using 24-hour BP monitoring [30] indicate that the dose-response
relationship of ARBs is linear. Therefore, significant improvements in BP control can be achieved by
increasing the dosage of the ARB.[25] This finding was confirmed by the fact that the wide majority of ARBs
have been further assessed for clinical activity and marketed at increased dosages.
5. Combination Therapy
The basic principles of clinical pharmacology should also be applied to combination therapy.
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Combination therapy is needed in the majority of hypertensive patients. Combination therapy may be
effective in patients who do not respond to monotherapy, and it is necessary to achieve BP control in
7580%of those with mild to moderate hypertension.[6] Furthermore, physiological and pharmacological
synergies justify the greater effectiveness of drug combinations (table II).
Table II. Rational combinations of antihypertensive drugs
Drug class First choice Second choice
ACE inhibitors Diuretics (thiazide or loop)1-Adrenoceptorantagonists
Calcium channel antagonists
AT1 receptor antagonists (angiotensin receptorblockers)
Diuretics (thiazide or loop)1-Adrenoceptorantagonists
Calcium channel antagonists (DHP) ACE inhibitors1-Adrenoceptorantagonists
AT1 receptor antagonists Central SNS modulators
-Adrenoceptor antagonists
Calcium channel antagonists (non-DHP) ACE inhibitors1-Adrenoceptorantagonists
AT1 receptor antagonists
-Adrenoceptor antagonists Diuretics (thiazide or loop)1-Adrenoceptorantagonists
Calcium channel antagonists(DHP)
Thiazide diuretics ACE inhibitors1-Adrenoceptorantagonists
AT1 receptor antagonists Central SNS modulators
-Adrenoceptor antagonistsa
a Documented negative metabolic effect.
AT1= angiotensin II type 1; DHP= dihydropyridine; SNS= sympathetic nervous system.
The 2007 ESH/ESC guidelines[5] recommend the use of two drug combinations as initial treatment in
hypertensive patients with a high initial BP or at high/very high CV risk due to the presence of organ
damage, diabetes, renal disease, or a history of CV disease. As previously discussed for monotherapy,
current guidelines recommend initiating treatment with two-drug combinations at low dosages (figure 1).
In many cases this is not pharmacologically correct, particularly considering that most combinations used in
clinical practice include drugs blocking the RAAS. These drugs can be used rationally in combination with
diuretics or calcium channel antagonists.
The combination of a RAAS blocker with a diuretic has been largely prescribed in hypertensive patients
because of effectiveness and tolerability, since ACE inhibitors or ARBs prevent the negative effects of
diuretics on electrolytes or metabolic profile. [31,32] In addition, there are many fixed combinations that are very
convenient to use, and can therefore improve patient compliance. The RAAS blocker should be given at full
dosages while the diuretic should be administered at low dosages (e.g. hydrochlorothiazide 12.5 mg/day or
indapamide 0.625 mg/day). Problems can arise when using fixed combinations that are not rational
according to the drugs' clinical pharmacology. Typical examples are the fixed combinations of ramipril 2.5
mg with hydrochlorothiazide 12.5 mg, or perindopril 2mg with indapamide 0.625 mg. In these cases, theantihypertensive effect is almost totally sustained by the diuretic, while the beneficial effects of the ACE
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inhibitors are very modest. It is far more convenient to use fixed combinations combining an ACE inhibitor at
full dose (e.g. enalapril 20 mg, lisinopril 20 mg, benazepril 20 mg) with a low dose of diuretic (e.g.
hydrochlorothiazide 12.5 mg). It is worth noting that no fixed combination is available with ramipril 10 mg,
the dose that should be prescribed more often.
In recent years, there has been a great deal of interest around the combination of an ACE inhibitor and acalcium channel antagonist, as a consequence of the important results of the ASCOT (Anglo-Scandinavian
Cardiac Outcomes Trial-Blood Pressure Lowering Arm)[33] and ACCOMPLISH (Avoiding Cardiovascular
Events Through Combination Therapy in Patients Living With Systolic Hypertension)[34] trials. These studies
have demonstrated that this combination is superior to the combination of a -blocker with a thiazide
diuretic and an ACE inhibitor with a thiazide diuretic, respectively.
Based on the results of the ACCOMPLISH trial (figure 4), the combination of an ACE inhibitor with a calcium
channel antagonist should be considered a first-line treatment in hypertensive patients. It is also important
to underline that administration of an ACE inhibitor reduces the principal side effect of calcium channel
antagonists, i.e. ankle edema.[35]
Figure 4. Main results from the ACCOMPLISH study. The combination of an ACE inhibitor
(benazepril) with a calcium channel antagonist (amlodipine) was more effective (relative risk reduction
of 20%) for reducing primary events (composite of death from cardiovascular causes, nonfatal
myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac
arrest, and coronary revascularization) than the combination of an ACE inhibitor (benazepril) with a
diuretic (hydrochlorothiazide). Adapted from Jamerson et al [34].
On this basis, in the near future several fixed combinations of RAAS antagonists and calcium channel
antagonists will become available.[36] The availability of fixed combinations of ACE inhibitors with calcium
channel antagonists rather than with diuretics is crucial, as significant improvements in compliance, and
therefore in BP control, can be achieved with the fixed-combination approach. [37] It is important that the
expert physician chooses the right formulation. This should be a RAAS blocker at full dose and a calcium
channel antagonist at low dose when starting treatment, while a formulation with both drugs at full dose is
crucial to reach target BP values.
6. Conclusions
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BP normalization is crucial to reduce the CV risk of hypertensive patients. However, while BP reduction is a
fairly easy target, BP normalization is much more difficult to achieve. One of the main reasons for the lack of
efficacy of pharmacological treatment is that drugs are very often not administered at the correct dosage.
This is particularly the case for ACE inhibitors, compounds characterized by a non-linear dose-response
curve. A low dose of an ACE inhibitor has the same potency as a high dose but a shorter duration of action.
If a low dosage is administered to a hypertensive patient, it causes BP fluctuations, which have beenassociated with negative CV outcomes.
It is therefore important to be aware of the clinical pharmacology of antihypertensive drugs in order to
choose not only the class or the molecule best suited to the clinical characteristics of the patient, but also
the correct dosages to ensure effective and homogeneous 24-hour BP reduction.
A correct pharmacological approach is fundamental to obtain the maximal beneficial effect, i.e. BP
normalization and the consequent reduction in CV risk, from antihypertensive treatment.
References
1. Lopez AD, Mathers CD, Ezzati M, et al. Global and regional burden of disease and risk factors,
2001: systematic analysis of population health data. Lancet 2006; 367 (9524): 174757
2. Kotseva K, WoodD, De Backer G, et al. Cardiovascular prevention guidelines in daily practice: a
comparison of EUROASPIRE I, II, and III surveys in eight European countries. Lancet 2009; 373
(9667): 92940
3. Ezzati M, Lopez AD, Rodgers A, et al. Selected major risk factors and global and regional burden
of disease. Lancet 2002; 360 (9343): 134760
4. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to
vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective
studies. Lancet 2002; 360 (9349): 190313
5. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events:
results of prospectively-designed overviews of randomised trials. Lancet 2003; 362 (9395):
152735
6. Mancia G, De Backer G, Dominiczak A, et al. 2007 guidelines for the management of arterial
hypertension: the task force for the management of arterial hypertension of the European Society
of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25 (6):
110587
7. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension
management: a European Society of Hypertension Task Force document. J Hypertens 2009; 27
(11): 212158
8. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide
data. Lancet 2005; 365 (9455): 21723
9. Mancia G, Pessina AC, Trimarco B, et al. Blood pressure control according to new guidelines
targets in low-to high-risk hypertensives managed in specialist practice. J Hypertens 2004; 22 (12):
238796
10. Ezzati M, Oza S, Danaei G, et al. Trends and cardiovascular mortality effects of state-level blood
pressure and uncontrolled hypertension in the United States. Circulation 2008; 117 (7): 90514
11. Mancia G, Grassi G. Systolic and diastolic blood pressure control in antihypertensive drug trials. J
Hypertens 2002; 20 (8): 14614
12. Ghiadoni L, Bruno RM, Stea F, et al. Central blood pressure, arterial stiffness, and wave reflection:
new targets of treatment in essential hypertension. Curr Hypertens Rep 2009; 11 (3): 1906
13. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and
treatment: a scientific statement from the American Heart Association Professional Education
Committee of the Council for High Blood Pressure Research. Hypertension 2008; 51 (6):
140319
-
8/3/2019 Administrarea Corecta a Antihipertensivelor in Functie de Farmacocinetica
11/12
14. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart
failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N
Engl J Med 1987; 316 (23): 142935
15. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril,
on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study
Investigators. N Engl J Med 2000; 342 (3): 14553 16. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable
coronary artery disease: randomised, double-blind, placebocontrolled, multicentre trial (the
EUROPA study). Lancet 2003; 362 (9386): 7828
17. Salvetti A, Di Venanzio L, Arrighi P, et al. Trough:peak ratio of the blood pressure response to
angiotensin converting enzyme inhibitors. J Hypertens 1994 Suppl.; 12 (8): S914; discussion
S945
18. Parati G, Pomidossi G, Albini F, et al. Relationship of 24-hour blood pressure mean and variability
to severity of target-organ damage in hypertension. J Hypertens 1987; 5 (1): 938
19. Frattola A, Parati G, Cuspidi C, et al. Prognostic value of 24-hour blood pressure variability. J
Hypertens 1993; 11 (10): 11337
20. Frick MH, McGibney D, Tyler HM. A dose-response study of amlodipine in mild to moderatehypertension. J Intern Med 1989; 225 (2): 1015
21. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting
their interchangeability. Hypertension 2004; 43 (1): 49
22. Elliott HL, Meredith PA, Vincent J, et al. Clinical pharmacological studies with doxazosin. Br J Clin
Pharmacol 1986; 21 Suppl. 1: 27S-31S
23. Salvetti A, Di Venanzio L. Clinical pharmacology of long-acting calcium antagonists: what
relevance for therapeutic effects? J Cardiovasc Pharmacol 1994; 23 Suppl. 5: S314
24. Davies RO, Gomez HJ, Irvin JD, et al. An overview of the clinical pharmacology of enalapril. Br J
Clin Pharmacol 1984; 18 Suppl. 2: 215S-29S
25. Smith DH. Dose-response characteristics of olmesartan medoxomil and other angiotensin receptor
antagonists. Am J Cardiovasc Drugs 2007; 7 (5): 34756 26. Remme WJ, McMurray JJ, Hobbs FD, et al. Awareness and perception of heart failure among
European cardiologists, internists, geriatricians, and primary care physicians. Eur Heart J 2008; 29
(14): 173952
27. Drugs.com: drug information online. Enalapril [online]. Available from URL:
http://www.drugs.com/pro/enalapril-tablets.html [Accessed 2010 Nov 1]
28. Drugs.com: drug information online. Ramipril [online]. Available from URL:
http://www.drugs.com/pro/ramipril.html [Accessed 2010 Nov 1]
29. Neutel JM. Effect of the renin-angiotensin system on the vessel wall: using ACE inhibition to
improve endothelial function. J Hum Hypertens 2004; 18 (9): 599606
30. Fogari R, Ambrosoli S, Corradi L, et al. 24-hour blood pressure control by once-daily administration
of irbesartan assessed by ambulatory blood pressure monitoring: Irbesartan MulticenterInvestigators' Group. J Hypertens 1997; 15 (12 Pt 1): 15118
31. Weinberger MH. Blood pressure and metabolic responses to hydrochlorothiazide, captopril, and
the combination in black and white mild-to-moderate hypertensive patients. J Cardiovasc
Pharmacol 1985; 7 Suppl. 1: S525
32. Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens
2006; 24 (1): 310
33. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive
regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide
as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm
(ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366 (9489): 895906
34. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide forhypertension in high-risk patients. N Engl J Med 2008; 359 (23): 241728
-
8/3/2019 Administrarea Corecta a Antihipertensivelor in Functie de Farmacocinetica
12/12
35. Salvetti A, Innocenti PF, Iardella M, et al. Captopril and nifedipine interactions in the treatment of
essential hypertensives: a crossover study. J Hypertens Suppl. 1987; 5 (4): S13942
36. Chatzikyrkou C, Haller H, Menne J. The role of fixed-dose combinations in the management of
hypertension: focus on lercanidipine-enalapril. Expert Opin Pharmacother 2009; 10 (11):
183340
37. Dickson M, Plauschinat CA. Compliance with antihypertensive therapy in the elderly: a comparisonof fixed-dose combination amlodipine/benazepril versus component-based free-combination
therapy. Am J Cardiovasc Drugs 2008; 8 (1): 4550
AcknowledgmentsThe authors thank Claire Byrne, from inScience Communications (a Wolters Kluwer business), who provided native Englishlanguage assistance. This assistance was funded by Recordati.
Prof. Taddei has received honoraria for serving on the speakers bureau for: Servier International, Boehringer Ingelheim,Menarini, Recordati International, Sanofi-Aventis, and Pfizer. Dr Ghiadoni has received honoraria for serving on the speakersbureau for Recordati and Servier. Dr Bruno has no conflicts of interest that are directly relevant to the content of this review.Am J Cardiovasc Drugs. 2011;11(1):13-20. 2011 Adis Data Information BV