Download Alpha Adrenergic Blockers in the Treatment of Hypertension – A

30
supplement to Journal of the association of physicians of india • Published on 1st of every month 1st september, 2014 • VOL. 62
Alpha Adrenergic Blockers in the Treatment of
Hypertension – A Nephrologist’s Perspective
Abhijit Taraphder*
Introduction
W
e know by now that hypertension
is associated with considerable
cardiovascular morbidity. That control of
blood pressure offers freedom from many
such complications is also proven. But a
lot more remains to be known about the
enigma named hypertension.
We s t i l l d o n o t k n o w t h e e x a c t
pathogenesis of hypertension; every
single author differs in defining
hypertension. Little is known about
the optimum goal of treatment. But
maximum controversy centres on the
choice of anti-hypertensive drug. With
each new recommendation, some new
group of drugs gets a nod while some
drugs fall from the grace.
In nephrology practice, while selecting
the appropriate anti-hypertensive agent,
the clinician has to keep in mind two
aspects in addition to achieving the
target blood p ressure ( BP). First ly ,
an agent should be chosen which is
renoprotective. It will preserve renal
function, thereby preventing or retarding
the invariable downhill course of the
disease. At the same time, it will not
adversely affect the internal environment.
Hence an agent which may aggravate
or precipitate hyperkalaemia is not
particularly welcomed by the nephrology
community.
The group of drugs called alpha
adrenergic blockers does not figure
as the preferred agent in most of the
recommendations of late. 1
Mechanism of Action
Senior Consultant and Head
Department of Nephrology,
Apollo Gleneagles Hospital,
Kolkata – 700025
*
Sympathetic nervous system plays
a major role in the pathogenesis of
hypertension. Blockade of alpha-1
receptors by appropriate agents provides
a rational approach to the treatment of
hypertension by inhibiting the binding
of noradrenaline to the said receptors,
thereby promoting smooth muscle cell
relaxation, reduced vascular tone and
decreased peripheral resistance. 2 The net
result is control of blood pressure.
Blood Pressure Control
The effects of alpha blockers have been
extensively studied both as monotherapy
and add on therapy. The results were
encouraging. Both prazosin and
doxazosin decreased blood pressure in
approximately 70% patients following a
12 week treatment period. 3 Alfuzosin was
equally effective as propranolol when
used as first line agent. 4 Among patients
who had not responded to monotherapy
with diuretics, beta blockers, calcium
channel blockers and ACE inhibitors,
the addition of terazosin resulted in
significant BP reduction. 5
In the treatment of mild hypertension
study (TOMHS) after four years of follow
up, initial therapy with standard release
doxazosin (1-2 mg per day) reduced
systolic and diastolic BP by 13.4 and
11.2 mm Hg respectively, compared with
mean reductions of 8.6 mm Hg for both
systolic and diastolic BP among those
who received placebo. 6
Early Criticisms
The two important limitations
encountered with alpha blockers earlier
were postural hypotension and failure
to achieve round the clock BP control.
These were largely overcome by the
d e ve l o p m e n t o f c o n t r o l l e d r e l e a s e
formulations such as prazosin and
doxazosin gastro intestinal therapeutic
system (GITS).These formulations were
successful in minimising the side effects
by slowing absorption and reducing
fluctuations in plasma concentration. 7
Success Story of GITS
Prazosin GITS was shown to have
similar BP lowering efficacy as enalapril
in hypertensive patients with diabetes
supplement to Journal of the association of physicians of india • Published on 1st of every month 1st se ptember, 2014 • VOL. 62
mellitus in an Indian population. 8 In a substudy of the
HALT trial, evening dosing with doxazosin reduced
both daytime and night time systolic and diastolic BP. 9
Doxazosin GITS achieved more effective 24 hour BP
control when administered at night (either alone or as
add on therapy) in another study. 10 In the randomised
double blind doxazosin GITS as add on therapy in
hypertension: an efficacy and safety (GATES) study
doxazosin GITS (4 mg per day, titrated to 8 mg if
required) or placebo was added to the existing antihypertensive therapy of patients with uncontrolled
BP. After 6 weeks treatment, BP control (defined as <
140/90 mm Hg) was achieved in 37.3% in the doxazosin
group, compared with 10.7% in those who received
placebo. 11
In the ASOCIA study, when doxazosin GITS (4
mg per day, titrated to 8 mg if required) was added
to the existing medications in a study population of
3631 spanish patients , target BP (<140/90 mm Hg) was
achieved in 39% at 4 weeks rising to 61% at 16 weeks. 12
Metabolic Effects
Alpha blockers have been shown to affect favourably
various metabolic parameters , namely total cholesterol,
low density lipoprotein (LDL) cholesterol , high
density lipoprotein (HDL) cholesterol and plasma
insulin levels, when used alone or in a combination. In
107 normotensive individuals with impaired glucose
tolerance, doxazosin compared with placebo, from
baseline to 6 months, resulted in a 6.5% reduction in
total cholesterol, 9.8% reduction in LDL cholesterol,
8.3% increase in HDL cholesterol, 19% reduction in
triglyceride, and 28% reduction in fasting plasma
insulin. 13 It is proposed that the increase in HDL
cholesterol by doxazosin is mediated through gene
transcription and is independent of its alpha blocking
action. 14
Safety and Tolerability
The most common adverse events observed in
patients receiving alpha blockers are dizziness,
headache and asthenia. Patients may also encounter
postural hypotension and syncope. Erectile
dysfunction, though reported rarely, maybe the reason
behind discontinuation of the drug. However, the
GITS preparation is well tolerated and the reported
incidence of discontinuation due to side effects is less. 15
The ALLHAT Outcome
The antihypertensive and lipid lowering treatment
to prevent heart attack trial (ALLHAT) was designed
to compare the effects of a thiazide diuretic
(chlorthalidone) with an alpha blocker (doxazosin),
a calcium channel blocker and an ACE inhibitor
among hypertensive patients aged 55 years or more
31
with at least one other cardiovascular risk factor. 16
Though follow up was planned for 6-8 years, the
doxazosin arm was discontinued prematurely based
on a significantly higher incidence of combined
cardiovascular disease events ( a secondary end point)
in the doxazosin arm. Major cardiovascular events
were 25% more frequent among those who were
assigned doxazosin, a result driven by higher rates
of stroke and particularly congestive heart failure.
Doxazosin was also associated with less effective BP
control compared to chlorthalidone.
The results of ALLHAT generated much debate.
The validity of heart failure diagnosis was questioned.
It was also postulated that the early divergence of
the event curves for heart failure represented the
unmasking of symptoms of heart failure due to
withdrawal of diuretics in the participants who were
on antihypertensive therapy prior to randomisation. 17
Inspite of all the criticisms and questions about
ALLHAT, in the seventh report of the joint national
committee on prevention, detection, evaluation and
treatment of high blood pressure (JNC 7) guidelines,
alpha blockers were not recommended for the routine
treatment of hypertension.
The Anglo – Scandinavian Cardiac
Outcomes Trial (ASCOT)
ASCOT was a multi centre international randomised
trial conducted in 19,257 patients aged 40 to 79 years
with hypertension and additional cardiovascular risk
factors but no history of coronary heart disease. 18 In
an observational analysis, the effects of doxazosin
GITS were evaluated in 10069 patients (32% having
diabetes).
During a median of 12 months of uninterrupted
therapy, mean BP fell by almost 12/7 mm Hg and target
BP was achieved in 30% patients. During a median of
9 months of uninterrupted doxazosin treatment, there
were significant reductions in total cholesterol (4.7%),
LDL cholesterol (5.5%) and triglyceride (9.1%).
But the most significant observation was the crude
heart failure rate, which was 1.5% among those who
received doxazosin as against 1.54% among the
remainder. This was despite the fact that recipients
of doxazosin had more severe hypertensive disease
(higher systolic BP and prevalence of left ventricular
hypertrophy) at study entry compared to the rest of
the study population.
Alpha Blockers in Renal Disease
Chronic kidney disease (CKD) has been reported
to be accompanied by increased sympathetic activity,
which partly explains the augmented cardiovascular
risk in CKD. Microalbuminuria is now considered a
surrogate marker for cardiovascular risk and is used
32
supplement to Journal of the association of physicians of india • Published on 1st of every month 1st september, 2014 • VOL. 62
to screen for CKD. Sympathetic nerve activity is one
of the mechanisms of morning hypertension. Alpha
blockers when taken just before going to bed are
reported to decrease morning BP surge. In the Japan
Morning Surge – 1 (JMS-1) study, the effects of the
alpha blocker doxazosin was tested in 611 patients
with morning hypertension in terms of BP lowering
and improvement in microalbuminuria. In the study
conducted by 60 doctors at 16 institutions during a
period from 1 st August 2003 to 30 th August 2005, there
was a 10 mm Hg reduction of self measured systolic
BP in the morning and 5 mm systolic BP reduction
in the evening. The urinary albumin /creatinine ratio
was more markedly reduced in the doxazosin group
(-3.4 vs 0.0 mg/g) compared with the control group. 19
When the effects of doxazosin were assessed in
type 2 diabetic patients with macroalbuminuria, it was
observed that doxazosin could reduce both waking
and sleeping BP to the same extent over the 24 hour
period. As a result, the sleeping/waking BP ratios did
not alter. 20
Six months continuous treatment with doxazosin
treatment in a titrated dose not only reduced
proteinuria (from 1.8 g/day to 1.3 g/day), the
glomerular filtration rate (GFR) improved from 24.5
ml/min to 29.7 ml/min and mean serum creatinine
dropped from 3.0 mg/dl to 2.5 mg/dl. It is proposed
that the glomerular protective action of doxazosin is
mediated through its inhibition of norepinephrine
induced vasoconstrictive activity in both the afferent
and efferent arteries of the kidney. 21
That prazosin is an effective antihypertensive agent
in all types of hypertensive dialysis patients, either
alone or in combination, with minimal side effects,
has been shown in more than one studies. 22,23
The incidence of hypertension ranges from 60% to
80% in renal transplant recipients. Increased vascular
resistance is a prominent feature of post transplant
hypertension. Alpha blockers which act through
peripheral vasodilatation, thereby reducing peripheral
resistance, interfere with adrenergic vasoconstrictive
mechanism, may be particularly beneficial in post
transplant hypertension. The trough to peak (T/P) ratio
is a single parameter that describes the consistency and
duration of an anti-hypertensive drug’s action. In a
population of cadaveric kidney transplant recipients,
the T/P ratio of more than 50% in 24 hour BP monitoring
was observed with doxazosin GITS. 24 There were no
metabolic adverse effects either. Beneficial effects in
6 renal transplant recipients could be observed with
prazosin treatment in another study. 25
In a 4 week prospective open multi centre study
conducted in Indian population both peak urinary
flow rate and IPSS (international prostate symptom
score) improved in 75 male patients aged between 50
and 75 years having symptomatic benign prostatic
hyperplasia, when treated with prazosin GITS 2.5 mg
increased to 5 mg at bedtime if required. 26
Conclusion
Alpha adrenergic blockers are a group of agents with
time-tested efficacy in blood pressure control. They are
effective in mild to moderate hypertension, can be used
alone or in combination. The GITS formulation can be
used as once daily formulation preferably at night.
They have favourable effect on metabolic profile (e.g.
lipids and insulin sensitivity) and are well tolerated.
The most commonly encountered side effects are
dizziness and postural hypotension which have been
largely overcome by the night time administration of
the GITS formulation.
From a nephrologist’s perspective, alpha blockers
have been proved to be effective not only in controlling
BP but also in reducing microalbuminuria, which is a
surrogate marker of CKD progression. In that sense
these agents are renoprotective. They have been tried
successfully in dialysis and transplant population. The
metabolic neutrality is an added advantage. Treatment
with alpha blockers is not associated with serious side
effects like hyperkalaemia.
Inspite of all these advantages, these group of
agents do not find a place in JNC recommendations.
European Society of Hypertension, European Society
of Cardiology, British Hypertension Society, National
Institute of Health and Clinical Excellence, in short
all the leading guidelines are either silent or have
shown lack of interest in alpha blockers. The major
driving force, in all likelihood, is the adverse outcome
encountered in the ALLHAT. Though ASCOT tried
to alleviate some of the apprehensions about the use
of alpha blockers, questions continued to be raised
about the outcome of ASCOT, namely inadequacies
of observational data, possible sources of bias, the
presence in each arm of ASCOT of a drug used to
treat heart failure (e.g. diuretics, ACE inhibitors),
differences between use of doxazosin as third or first
line therapy and so on. That trials like ASCOT and
ASOCIA failed to convince the medical fraternity
about the potential benefits of alpha blockers is
reflected in various recommendations.
Yet, to a nephrologist, they are a group of agents
which demand a re-appraisal. Alpha blockers can be
used in refractory cases as add on therapy, especially
in the 50 plus age group with benign prostatic
hyperplasia. They can also be considered in those with
mild to moderate hypertension, who have repeated
hyperkalaemia with ACE inhibitor or ARB use, and
who develop worrisome peripheral oedema due to
calcium channel blockers. The theoretical benefit of
renoprotection will also tilt the balance in favour of
alpha blockers.
Actually, though alpha blockers are in use for long,
supplement to Journal of the association of physicians of india • Published on 1st of every month 1st se ptember, 2014 • VOL. 62
they did not get the benefit of having a well controlled
trial to counter the observations of ALLHAT. Indian
data are also inadequate. Hence, a relook into the
possible use of alpha blockers is only possible if multicentre randomised trials are conducted in the Indian
population.
References
1.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr,
et al. Seventh report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure.
Hypertension 2003;42:1206–1252.
2.
Chapman N, Chen C-Y, Fujita T, Hobbs F D, Kim S-J, Staessen J A,
Tanomsup S, Wang J-G, and Williams B. Time to re-appraise the
role of alpha-1 adrenoceptor antagonists in the management of
hypertension? J Hypertens 2010;28:1796–1803.
3.
Fukiyama K, Omae T, Iimura O, Yoshinaga K, Yagi S, Inagaki Y, et al.
A double-blind comparative study of doxazosin and prazosin in the
treatment of essential hypertension. Am Heart J 1991;121:317–322.
4.
Sega R, Marazzi ME, Bombelli M, Vulpis V, Antonacci A, Leto di Priolo
S, et al. Comparison of the new alpha-1 blocker alfuzosin with
propranolol as first-line therapy in hypertension. Pharmacol Res
1991;24:41–52.
5.
Itskovitz HD. Alpha 1-blockade for the treatment of hypertension:
a megastudy of terazosin in 2214 clinical practice settings. Clin Ther
1994;16:490–504.
6.
Neaton JD, Grimm RH Jr, Prineas RJ, Stamler J, Grandits GA, Elmer PJ,
et al. Treatment of Mild Hypertension Study. Final results. J Am Med
Assoc 1993;270:713–724.
7.
Chung M, Vashi V, Puente J, Sweeney M, Meredith P. Clinical
pharmacokinetics of doxazosin in a controlled-release gastrointestinal
therapeutic system (GITS) formulation. Br J Clin Pharmacol
1999;48:678–687.
8.
Joglekar SJ, Nanivadekar AS. A randomized, controlled, multicenter
study to compare prazosin GITS with enalapril in hypertensive patients
with diabetes mellitus. J Assoc Physicians India 1998;(Suppl1):52–62.
9.
Kario K, Schwartz JE, Pickering TG. Changes of nocturnal blood
pressure dipping status in hypertensives by nighttime dosing of
alpha-adrenergic blocker, doxazosin: results from the HALT study.
Hypertension 2000;35:787–794.
10. Hermida RC, Calvo C, Ayala DE, Dominguez MJ, Covelo M, Fernandez
JR, et al. Administration-time-dependent effects of doxazosin GITS
on ambulatory blood pressure of hypertensive subjects. Chronobiol
Int 2004;21:277–296.
11. Black HR, Keck M, Meredith P, Bullen K, Quinn S, Koren A. Controlled
release doxazosin as combination therapy in hypertension: the GATES
study. J Clin Hypertens (Greenwich) 2006;8:159–166.
12. de Alvaro F, Hernandez-Presa MA, ASOCIA Study. Effect of
doxazosin gastrointestinal therapeutic system on patients with
uncontrolled hypertension: the ASOCIA Study. J Cardiovasc Pharmacol
2006;47:271–276.
13. Derosa G, Cicero AF, D’Angelo A, Ragonesi PD, Ciccarelli L, Fogari
E, et al. Synergistic effect of doxazosin and acarbose in improving
metabolic control in patients with impaired glucose tolerance. Clin
Drug Investig 2006;26:529–539.
33
14. Iwamoto N, Abe-Dohmae S, Ayaori M, Tanaka N, Kusuhara M, Ohsuzu
F, et al. ATP-binding cassette transporter A1 gene transcription is
downregulated by activator protein 2alpha. Doxazosin inhibits
activator protein 2alpha and increases high-density lipoprotein
biogenesis independent of alpha1-adrenoceptor blockade. Circ Res
2007;101:156–165.
15. Os I, Stokke HP. Effects of doxazosin in the gastrointestinal therapeutic
system formulation versus doxazosin standard and placebo in mildto-moderate hypertension. Doxazosin Investigators’ Study Group. J
Cardiovasc Pharmacol 1999;33:791–797.
16. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. Major cardiovascular events in hypertensive patients
randomized to doxazosin vs. chlorthalidone: the Antihypertensive
and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
J Am Med Assoc 2000;283:1967–1975.
17. Poulter N, Williams B. Doxazosin for the management of hypertension:
implications of the findings of the ALLHAT trial. Am J Hypertens
2001;14:1170–1172.
18. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al.
Rationale, design, methods and baseline demography of participants
of the Anglo-Scandinavian Cardiac Outcomes Trial. J Hypertens
2001;19:1139–1147.
19. Kario K, Matsui Y, Shibasaki S, Eguchi K, Ishikawa J, Hoshide S,
Ishikawa S, Kabutoya T, Schwartz J, Pickering T, Shimada K on
behalf of the Japan Morning Surge-1 (JMS-1) Study Group: An
alpha-adrenergic blocker titrated by self-measured blood pressure
recordings lowered blood pressure and microalbuminuria in patients
with morning hypertension: the Japan Morning Surge-1 Study. J
Hypertens 2008;26:1257–1265.
20. G. Yasuda, K. Hasegawa, T. Kuji, N. Ogawa, G. Shimura, S. Umemura and
O. Tochikubo. Effects of doxazosin on ambulatory blood pressure and
sympathetic nervous activity in hypertensive Type 2 diabetic patients
with overt nephropathy. Diabetic Medicine 2005;22:1394–1400
21. Mori Y, Matsubara H, Nose A, Shibasaki Y, Masaki H, Kosaki A, Okigaki
M, Fujiyama S, Tanaka-Uchiyama Y, Hasegawa T, Iba O, Tateishi E,
Amano K, Iwasaka T. Safety and availability of doxazosin in treating
hypertensive patients with chronic renal failure. Hypertens Res
2001;24:359–363.
22. Harter, H.R. and Delmez, J.A.: Effects of prazosin in the control of blood
pressure in hypertensive dialysis patients. Journal of Cardiovascular
Pharmacology 1979l(Suppl):S43–S55
23. Meltzer VN, Goldberg AP, Tindira CA, Naumovich AD, Harter HR. Effects
of prazosin and propranolol on blood pressure and plasma lipids in
patients undergoing chronic hemodialysis. Am J Cardiol 1984;53:40A–
45A
24. Martínez Castelao A, Ibernon M, Sarrias X, Sanz V, Moreso F, Rama I,
Grinyó JM. Doxazosin GITS trough to peak ratio and 24-hour blood
pressure monitoring in the management of hypertension in renal
transplant patients. Transplantation proceedings 2003;35:1736-1738.
25. Curtis JR, Bateman FJA: Use of prazosin in management of
hypertension in patients with chronic renal failure and in renal
transplant recipients. Br Med J 1975;4:432–434.
26. Bapat S S, Raina S, Nagasubramanyam S, Anand V J, Patankar S, Thatte
S W. Prazosin GITS in patients with benign prostatic hyperplasia: A 4
week prospective open multi centre study. Indian Journal of Urology
2004;(Suppl6):20-28.