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Alpha Adrenergic Antagonists- An anti hypertensive which is under utilised?

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Sarin S M Sarosh Kumar K K

Academy of Medical Sciences, Pariyaram, Kannur, Kerala, India Academy of Medical Sciences, Pariyaram Kannur Kerala.
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 Annals Medicus
Online Indexed Medical Journal with ISSN No 2348 -3970
Vol 2; Issue 02: April 2015
REVIEW ARTICLE

Alpha Adrenergic Antagonists-

An anti hypertensive which is under utilised?
Sarin S M1, Balakrishnan Valliyot1, Sarosh Kumar K K1, Kadeeja Beevi B1

Abstract

Hypertension is one of the common disease that results in significant mortality and morbidity world
over. Adequate control of hypertension is an uphill task for primary care physician. Alpha adrenergic
antagonists are drugs that are available in the anti hypertensive armamentarium since 1970s. The safety
and efficacy of the drug was mired in controversies due to the reports of relative increase in incidence
of heart failure when used as a first line drug. The recent guidelines are ambiguous in their
recommendations of its usage as an anti hypertensive. This article intends to review the data that are
present before us with regard to alpha adrenergic antagonists so that clinicians could make a well
informed decision about using this precious group of drug in their day to day practice.

Introduction this article we are trying to review the use of

alpha 1 antagonists in treating hypertension.
Hypertension is one of the most common This group of drug are commonly used as an
disease that affect about 40% of world adult add on drug for treating uncontrolled
population above the age of 25 years. Every hypertension in India and it is imperative on the
year it is responsible for an estimated 7.5 part of all primary care physicians to be
million death worldwide and about 57 million acquainted with all the data available regarding
disability adjusted life years1. It is one of the the drug.
major cause of stroke, renal and cardiovascular
diseases. Several studies reported that almost The pathogenesis of essential hypertension has
two third of the hypertensive patients are either many factors including increased activity of
untreated or under treated2. This can add on sympathetic nervous system resulting in
greatly to the morbidity and mortality of generalised increase in total peripheral
hypertensive patients. So tighter control of resistance, increased vascular sensitivity to
hypertension is very essential and this need catecholamines and other vasoactive agents,
appropriate use of anti hypertensive agents. In increased activity of renin-angiotensin-
aldosterone systems and reduced local or
Corresponding Author: circulating vasodilatory substances3,4.
Dr Sarin S M
Alpha adrenergic receptor antagonists
Department of Medicine, Academy of Medical
Sciences, Pariyaram, Kannur, Kerala, India Alpha receptor is one of the two receptors
Email Id : [email protected]
through which the sympathetic nervous system
acts. The α-adrenergic receptors are further

www.annalsmedicus.com / Vol 2 ; Issue 2; 2015 April Page 1

subdivided into two distinct types: α 1 , most of In addition to its anti hypertensive effect α 1
which are located postjunctionally on the antagonists have an added positive effect on the
vascular smooth muscle cell producing lipid metabolism. Blockade of the α adrenergic
vasoconstriction and α 2, which are located pathway leads to increased capillary flow and
prejunctionally on the sympathetic nerve ending greater availability of lipoprotein lipase, which
having negative feed back on norepinephrine ultimately results in decreased plasma levels of
release into the synapse5,6. triglycerides and triglyceride-rich lipoproteins.
They have been shown to increase HDL levels,
Earlier non selective α adrenergic antagonists decrease total cholesterol and triglyceride levels,
were the first group of drugs to be tried for and increase the HDL cholesterol/total
hypertension control. But due to the cholesterol ratio10. Some studies also reported
antagonising action of α2 receptor blockade improved insulin resistance in diabetic
over the α 1 blockade action this group of drugs hypertensive patients treated with doxazosin11.
were not suitable for hypertension control. Use
of selective α 1-adrenergic receptor blocker Alpha-blockers are well absorbed after oral
made physiologic and therapeutic sense as administration. The are usually extensively
blockade of the α1 adrenergic receptors causes metabolised in liver and only a very small
the relaxation of vascular smooth muscle amount of unchanged drug pass through urine.
leading to a reduction in blood pressure. These The main difference between various agents is
agents selectively block the α1 adrenergic in elimination half-life. Indoramin and prazosin
receptor but do not affect the prejunctional α 2 have shorter half life whereas doxazosin and
adrenergic receptors. Consequently, unwanted terazosin have much longer half life. They are
increased levels of norepinephrine are avoided generally well tolerated. It is known to produce
and thus undesirable cardiac and systemic some amount of first dose postural hypotension
effects of increased norepinephrine release are associated with reflex cardioacceleration and
circumvented. Initially, α 1 adrenergic receptor palpitation. It may also result in vasovagal
antagonists reduce arteriolar resistance and syncope. To circumvent this problem usually
increase venous capacitance which can causes a the drug is started as a smaller single night dose
sympathetically mediated reflex increase in which is later titrated up. Other adverse effects
heart rate and plasma renin activity. During reported include headache, oedema, drowsiness
long-term therapy, vasodilation persists, but and stress incontinence in women12.
cardiac output, heart rate, and plasma renin
activity return to normal. Renal blood flow is What does guidelines say about α1
unchanged during therapy with an α 1 receptor antagonists?
antagonist7.
Most of the major recent guidelines regarding
Alpha blockers have been in our hypertensive management are not enthusiastic in
armamentarium since 1976 when prazosin was their recommendation of α 1 antagonist as one
introduced in the market. Doxazosin , Indoramin of the first line drug. JNC 8 has not
, Prazosin and Terazosin are the commonly recommended α 1 antagonists as the first line
available α 1 adrenergic antagonists now. There therapy and is equivocal in its use as an
are numerous studies especially on doxazosin antihypertensive agent13. NICE guidelines states
about their effectiveness as an antihypertensive that in case of resistant hypertension in stage 4
agent8. Cochrane review conducted based on of therapy, if further diuretic therapy is not
limited number of published studies showed that tolerated or is contraindicated one can consider
α 1 antagonist can produce modest amount of use of an alpha antagonist14. ESH-ESC
blood pressure lowering and there was no guidelines recommends it to be used as a fourth
clinically meaningful differences in BP line therapy and reports a good response in case
lowering action among different α 1 blockers9. of resistant hypertension as an add on therapy15.
Trials and Controversies

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Many of the recent guidelines are shying away failure in the study16,18. The Anglo Scandinavian
in recommending α 1 antagonists as one of the Cardiac Outcome Trial(ASCOT) revealed a
first line drug in treating hypertension. This can different story. In ASCOT doxazosin GITS was
be partly due to modest blood pressure lowering added in a non randomized fashion as a third
efficacy of the drug and its adverse effect line drug if blood pressure was uncontrolled by
profile. But the result of one of the major trial the first and second line drugs. Heart failure was
namely, Antihypertensive and Lipid Lowering pre-specified as a secondary end point in
treatment to prevent Heart Attack ASCOT and diagnostic criteria set for it was
Trial(ALLHAT) have serious bearing on this. It more strict including positive investigation
suggested that initial therapy with the agent results. The data obtained in the study did not
produce worser cerebrovascular and heart show any excess of heart failure during almost
failure outcomes compared to diuretic therapy. 40 000 patient year exposure to doxazosin19. As
ASCOT used doxazosin only as a third line drug
ALLHAT compared the effectiveness of initial and also the fact that the patient under
antihypertensive therapy with three different doxazosin was selected in a non randomized
classes of anti hypertensive drugs namely, ACE fashion, it is difficult to directly compare these
inhibitor, Calcium channel blocker and α1 results with that of ALLHAT.
adrenergic antagonist with an established
treatment of thiazide diuretic in reducing a Specialised usage
primary end point of fatal coronary heart disease
or non fatal MI. During the study the doxazosin 1) Chronic kidney disease: Increased
arm( α antagonist) was stopped prematurely sympathetic activity is an important feature
because of reported excess of cardiovascular in renal disease, which significantly
events principally congestive cardiac failure contributes to development of hypertension
when compared to chlorthalidone16. When the and to target organ damage. α antagonists
subgroup treated with doxazosin was analysed can be used effectively in the management
and compared with those treated with of hypertension in renal disease due to their
chlorthalidone, it was noticed that though there good anti hypertensive efficacy, favourable
was a equal risk of coronary heart disease metabolic profile and lack of necessity for
deaths/non fatal MI , the combined major dose adjustments during dialysis.
Cardiovascular disease risk especially of 2) Benign prostatic hyperplasia: Since α 1
Congestive heart failure was significantly higher antagonists are known to be effective in
in doxazosin group17. management of LUTS in benign prostatic
hyperplasia, patients having the disease
Many commentators have pointed out the with coexisting hypertension may be
problems of study design that lead to the preferred to be treated with the drug.
findings of ALLHAT there after. It was pointed 3) Pheochromocytoma: α 1 antagonists are
out that the patients randomised in ALLHAT used along with β blockers in treatment of
were receiving previous anti hypertensive hypertensive crises in
treatment. The cross over of such patients ffrom pheochromocytoma18.
a pre existing treatment especially diuretic to a 4) Raynaud's disease and Scleroderma: Alpha
new drug without a “washout period” may have blockers are also useful in treatment of
unmasked the occult heart failure among them. diseases like raynaud's disease and
Another contentious issue was that the diagnosis scleroderma7.
of heart failure in ALLHAT was made based on
clinical criteria of presence of one symptom and Conclusion
one sign of heart failure. No investigation was Alpha adrenergic receptor antagonists have been
done to confirm the presence of cardiac failure long present in the armamentarium of anti
like ejection fraction estimation, BNP hypertensive agents but is one of the most under
estimation etc in majority of these cases. This utilized drug. With a positive impact on lipid
may have lead to an over estimation of the heart metabolism and insulin resistance this drug will

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definitely stand the test of time. But the conflicting diagnosing heart failure to have a definite conclusion
evidences regarding cardiovascular events associated in this regard. Till then the current recommendation
with the drug especially regarding the reported of usage of α 1 antagonist as a fourth line add on
increase in heart failure incidences have prevented it drug in treatment of resistant hypertension is what
from becoming one of the first line anti hypertensive we can follow. It can also be used in special
agent. There is a need for more extensive situations in which it offers additional benefit to the
randomised control trial with strict definition in patient

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ESH/ESC Guidelines for the management of Alpha-blockers in Hypertension : Reappraisal of
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2013; 34: 2159–2219 21. Chapman N , Chen CY , Fujita T et al. Time to
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cardiovascular events in hypertensive patients

1
Department of Medicine, Academy of Medical Sciences, Pariyaram, Kannur, Kerala, India

www.annalsmedicus.com / Vol 2 ; Issue 2; 2015 April Page 278

Figure & Tables

Figure 1: Alpha adrenergic receptors and its action

Figure obtained from the website http://www.cvpharmacology.com/vasoconstrictor/alpha-agonist

Table 1: Summary of major guidelines for use of alpha-1 adrenoceptor antagonists for hypertension

Guideline Year Recommendation

British Hypertension Society (BHS) 2011 Recommended as 4 th line therapy
Benign prostatic hyperplasia listed as a compelling
indication
European Society of Hypertension/European 2013 Recommends to be used as third line add-on therapy
Society of Cardiology (ESH/ESC) Benign prostatic hyperplasia listed as a specific indication
Joint British Societies, guidelines on prevention 2014 No recommendation for its use as anti hypertensive agent
of cardiovascular disease in clinical practice given
National Institute for Health and Clinical 2011 Recommended as fourth-line therapy
Excellence (NICE)
Eight Joint National Committee 2014 Included in list of oral antihypertensive agents but place in
on prevention, detection, evaluation and therapy not defined
treatment of high blood pressure (JNC 8)

Article Info:
Submitted on: Apr 14, 2015
Revised version accepted on: Apr 23,
How to cite this article : Sarin S M, Balakrishnan Valliyot, Sarosh Kumar K K, Kadeeja Beevi B: Alpha
Adrenergic Antagonists-An anti hypertensive which is under utilised? . Ann Med 2015; 2: Pg –275-279

www.annalsmedicus.com / Vol 2 ; Issue 2; 2015 April Page 279

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