European Geriatric Medicine (2023) 14:675–682

https://doi.org/10.1007/s41999-023-00813-x

SPECIAL ARTICLE

Centrally acting antihypertensives and alpha‑blockers in people at risk

of falls: therapeutic dilemmas—a clinical review
T. J. Welsh1,2,3 · A. Mitchell2,4,5

Received: 13 February 2023 / Accepted: 7 June 2023 / Published online: 12 July 2023
© The Author(s) 2023

Key summary points

Purpose To summarise the evidence for deprescribing alpha-blockers and centrally acting antihypertensives in older people
at risk of falls and to assist clinicians in deciding how to safely de-prescribe these agents.
Findings Alpha-blockers and centrally acting antihypertensives are no longer recommended for the treatment of hypertension
unless all other agents are contraindicated or not tolerated. Multiple tools identify these agents as potentially inappropriate
and recommend deprescribing. A number of protocols have been developed to safely guide deprescribing.
Message Safer antihypertensives are available that are associated with less adverse effects. Decision aids such as STOPP-
Falls can assist de-prescribing.

Abstract
Purpose The aim of this clinical review was to summarise the existing knowledge on the adverse effects of alpha-blockers
and centrally acting antihypertensives, the effect these may have on falls risk, and guide deprescribing of these medications.
Methods Literature searches were conducted using PubMed and Embase. Additional articles were identified by searching
reference lists and reference to personal libraries. We discuss the place of alpha-blockers and centrally acting antihyperten-
sives in the treatment of hypertension and methods for deprescribing.
Results Alpha-blockers and centrally acting antihypertensives are no longer recommended for the treatment of hypertension
unless all other agents are contraindicated or not tolerated. These medications carry a significant falls risk and non-falls risk-
associated side effects. Tools to aid and guide de-prescribing and monitoring of the withdrawal of these medication classes
are available to assist the clinician including information on reducing the risk of withdrawal syndromes.
Conclusions Centrally acting antihypertensives and alpha-blockers increase the risk of falls through a variety of mecha-
nisms—principally by increasing the risk of hypotension, orthostatic hypotension, arrhythmias and sedation. These agents
should be prioritised for de-prescribing in older frailer individuals. We identify a number of tools and a withdrawal protocol
to aid the clinician in identifying and de-prescribing these medications.

Keywords Falls · Deprescribing · Geriatric · Hypertension

Introduction
* A. Mitchell
[email protected] Hypertension is the most important cardiovascular risk
factor with the greatest impact on mortality [1–3]. Guide-
1
University of Bristol, Bristol, UK lines across the globe stress the importance of its detec-
2
RICE—The Research Institute for the Care of Older People, tion and treatment. High blood pressure is very common.
The RICE Centre, Royal United Hospital, Bath, UK Prevalence increases with age [4] and approximately
3
Royal United Hospitals Bath NHS Foundation Trust, Bath, 80% of those aged over 80 are hypertensive [5]. Multi-
UK ple large-scale randomised controlled trials (RCTs), such
4
Pharmacy Department, University Hospitals Plymouth NHS as the Hypertension in the Very Elderly Trial (HYVET),
Trust, Plymouth, UK have demonstrated health benefits from medications that
5
Department of Life Sciences, University of Bath, Bath, UK lower blood pressure [4, 6], and increasingly guidelines

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676 European Geriatric Medicine (2023) 14:675–682

are advocating lower and lower target blood pressures This review will explore the fall-related risks of alpha-
even amongst the oldest old [7–9]. However, there has blockers and centrally acting antihypertensives used to treat
been concern amongst clinicians, and within the academic hypertension. We provide an evidence review which may be
literature, that the benefits of antihypertensives may be of benefit to the clinician caught in a dilemma with regard
attenuated in frailer older people whilst the risks, such as to antihypertensive prescription. We review the factors that
falls, may be higher—thus creating a prescribing dilemma should be explored if de-prescribing is being considered and
[10]. Evidence associating falls with antihypertensives is outline a pointers for de-prescribing.
variable, reflecting the multitude of different antihyper-
tensives and variation in observational studies. Observa-
tional data highlight the period of medication initiation Medication review and reconciliation
or dose increase as being the period of greatest risk [11].
Alpha-blockers and centrally acting antihypertensives are Establishing the indication for the medication is important—
frequently highlighted as particularly problematic classes is the drug in question being used primarily for high blood
in cognitively and physically frailer people. pressure or for another condition? Alpha-blockers and cen-
However, alpha-blockers and centrally acting antihyper- trally acting antihypertensives are now not generally recom-
tensives still form part of the antihypertensive pharmaco- mended for the management of hypertension. They sit as
poeia albeit less prominently than in the past [12]. Their fourth-line agents in most guidelines. For alpha-blockers,
use is now restricted to that of an add-on therapy in cases of this is largely due to The ALLHAT trial which evaluated
resistant hypertension. Data on the extent of current usage the alpha-blocker doxazosin as first-line antihypertensive
are sparse. However, a large retrospective cohort study in therapy against diuretic treatment [16]. The trial had to be
Canada identified 2% of women aged ≥ 65 years with a diag- stopped early due to the increased risk of adverse cardiovas-
nosis of hypertension were prescribed an alpha-blocker [13]. cular events with doxazosin compared with chlorthalidone
Alpha-blockers for the management of prostatism are fre- [16]. However, some older patients may still be prescribed
quently prescribed and clinicians are more likely to encoun- over these agents as a legacy of historic prescribing trends
ter them in this context. This review will, however, focus on or due to intolerance of alternative antihypertensives. For the
alpha-blockers whose primary indication is hypertension. practicing clinician working with older people, these medi-
Centrally acting antihypertensives were widely used in the cations will more frequently be used for alternative diagno-
earliest decades of antihypertensive treatment when other ses. Thus, alpha-blockers will be most frequently encoun-
treatments were not available, but are less frequently used tered as a treatment for benign prostatic hyperplasia (BPH),
now, principally because of their poorer tolerability rela- and methyldopa will be encountered as part of the treatment
tive to the newer major classes of drugs [14]. The National regimen for Parkinson’s disease and related conditions.
Institute for Health and Care Excellence (NICE) no longer
mentions moxonidine or clonidine, and European and Inter-
national guidelines list moxonidine as an alternative 4th-line Measuring blood pressure and targets
antihypertensive only if spironolactone is not an option and
only under specialist use [7, 15]. Methyldopa for hyperten- Blood pressure must be assessed carefully. White coat
sion is advised for use only in pregnancy and so is unlikely hypertension affects around one in four older people [17],
to be encountered for this indication in clinical practice by and home blood pressure measurement or ambulatory meas-
the average geriatrician. However, clinicians will of course urements are preferred to those carried out in clinic as they
encounter patients prescribed methyldopa in the context of are more reliable [18] and more accurate [19]. Postural blood
Parkinson’s disease—a context which lies outside the scope pressure measurements must be carried out. In those with
of this discussion. orthostatic hypotension, standing blood pressure measure-
This clinical review was informed by a literature search ments should be used to guide therapy decisions [20]. The
conducted in PubMed and Embase initially in May 2022 European and UK guidelines suggest treating blood pres-
and updated in November 2022 including primary research, sure over 150/80 mmHg in those aged over 80 [7, 20] and in
systematic reviews and meta-analyses. Summary Product frailer groups, younger than 80 years (European guideline
Characteristics (SmPC), relevant hypertension guidelines, only) [7]. Guideline target blood pressure varies depending
personal reference libraries and the British National For- on co-morbidities and guideline. NICE recommends a target
mulary (BNF) were also utilised. Keywords for the searches clinic BP of < 150/80 mmHg [20], the ESC/ESH a systolic
included “falls”, “doxazosin”, “prazosin”, “terazosin”, of 130–139 mmHg if tolerated [7], and the International
“indoramin”, “moxonidine”, “clonidine”, “methyldopa”, Society of Hypertension guideline < 140/90 mmHg for the
“deprescribing”, “older adults” and appropriate variations people aged over 65 with the proviso to consider an indi-
of these terms. vidualised target in frailty and likely tolerability [15].

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The guidelines all try to provide an evidence-based Falls and fall‑related adverse events
rationale for the suggested regimes with medication
choice and blood pressure target adjusted to suit the The association between antihypertensives as a group and
comorbidities, e.g., heart failure. However, the typical fall risk is mixed. Multiple systematic reviews have failed
trial participant does not represent the frail, multi-morbid to provide a definitive answer. Stable long-term use of
older individual who the practicing geriatrician will most antihypertensives in otherwise well older people does not
frequently encounter [21]. It is also important to bear in appear to be associated with falls [25]. However, the risk
mind that in every randomised trial of antihypertensive of falling does increase for the 24-h period following anti-
medication, greater blood pressure control has led to a hypertensive initiation or dose increase, and this persists
reduction in adverse vascular outcomes such as stroke for 21 days in the case of diuretic antihypertensives [25].
or MI. The SPRINT trial demonstrated that greater con- Studies that have evaluated the association between
trol led to even greater improvements [22]. In the robust alpha-blockers and falls/fractures report variable findings.
older patient, there seems little reason to deviate from Hiremath and colleagues found no association with falls
guideline advice; however, in the frailer older adult—per- due to alpha-blockers in older women, hazard ratio (HR)
haps presenting with falls—the situation is different and 1.02 (95% CI 0.92–1.13) compared to other antihyperten-
attenuated target blood pressures or no target at all—with sives [13]. Whilst Welk and colleagues found a significant
a focus on outcomes meaningful for the patient becomes association between new prostate-specific alpha-blocker
more important. prescription for men and fracture odds ratio (OR) 1.16
(95% CI 1.07–1.21) and falls OR 1.14 (95% CI 1.07–1.21)
[26]. Meta-analyses by Ang and colleagues identified no
increased falls risk with alpha-blockers (OR 0.92 (95% CI
Cautions and contraindications 0.76–1.12) [27], whilst de Vries and Mansbart and col-
leagues found a trend towards increased risk (OR 1.62
As part of any medication review, it is important to con- (0.76–3.45) and OR 1.08 (95% CI 0.99–1.17) respectively)
sider any potential contraindications, and antihyperten- [28, 29].
sive medications are no exception. For alpha-blockers, We identified no recent systematic reviews of falls and
orthostatic hypotension and established heart failure centrally acting antihypertensives. The most recent study
(particularly if related to aortic stenosis) are contrain- identified was from 1999 (including papers published
dications [23]. The presence of these conditions should 1966–1996)—Leipzig and colleagues identified a trend
therefore prompt consideration of de-prescribing. For the towards an association between centrally acting antihy-
centrally acting antihypertensives, heart block and sick pertensives and falls OR 1.16 (95% CI 0.87–1.55) [30].
sinus syndrome are contraindications for both moxonidine The lack of more recent reviews on this drug class reflects
and clonidine [23]. Moxonidine is also contraindicated the move to alternative classes of antihypertensives with
in bradycardia and severe heart failure [23]. For methyl- better outcome data and fewer reported side effects. Where
dopa, depression should act as a contraindication as well centrally acting antihypertensives are discussed in the con-
as rarer problems, such as porphyria, paraganglioma and text of blood pressure in older people, it is to highlight the
pheochromocytoma [23]. All the centrally acting antihy- risks of orthostatic hypotension and significant side effects
pertensives and alpha-blockers are flagged by the ‘screen- [31]. Both STOPP and Beer’s criteria highlight them as
ing tool of older people's prescriptions (STOPP)’ criteria potentially inappropriate [24, 32].
as potentially inappropriate medications—particularly Both centrally acting antihypertensives and alpha-
in the context of postural hypotension—and should be blockers are associated with a number of adverse effects
reviewed accordingly [24]. known to be risk factors for falling. These can be grouped
Drug–drug interactions are common for methyldopa into cardiac, sleep-related and neuro-psychiatric. Table 1
with a higher risk of hypotension reported when used details the frequency of these events.
in conjunction with antihypertensives and other medica-
tions with hypotensive side effects (e.g., antipsychotics)
[23]. Moxonidine and clonidine have similar issues but
also have the potential to increase the risk of drowsiness, Cardiovascular side effects
confusion and CNS depression if used in conjunction with
other neuro-active medications [23]. The alpha-blockers Hiremath and colleagues found an association between
have multiple drug–drug interactions with increased alpha-blockers and hypotension HR 1.71 (95% CI
issues with hypotension reported with multiple drug 1.33–2.2) and hypotension-related events HR 1.1 (95%
classes [23].

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678 European Geriatric Medicine (2023) 14:675–682

Table 1  Incidence of adverse effects with alpha-blockers and centrally acting antihypertensives that could increase the risk of falls. Source: cog-
nitive enhancer SmPCs [58]
Anti-hyperten- Dizziness/vertigo Hypotension Syncope Drowsiness Blurred vision Sleep disorders Arrhythmia
sive

Alpha-blockers
Doxazosin +  +  + +  +  + +  + +  +  + + +  + +  +  +
Prazosin +  +  + +  +  + +  +  + +  +  + +  +  + +  + +  +
Terazosin +  +  + +  +  + +  + +  +  + +  +  + +  +  + +  +
Indoramin Frequency not Frequency not Frequency Frequency not No data Frequency not No data
known known not known known
known
Centrally acting antihypertensives
Moxonidine +  +  + +  + +  + +  +  + No data +  +  + +  +
Clonidine +  +  +  + +  +  +  + No data +  +  +  + Frequency not +  +  + +  +
known
Methyldopa Frequency not Frequency not No data Frequency not No data Frequency not Frequency not
known known known known known
+
  < 1/1000
++
1/100–1/1000
+++
1/10–1/100
++++
  > 1/10

CI 1.01–1.2) [13]. Chrischilles and colleagues reported with insomnia (incidence 0.8%), nightmares (incidence 2%),
that up to 50% of people given either terazosin, doxazosin mild psychoses and depression (incidence 3.6%) [39, 42].
or prazosin for BPH had to discontinue the alpha-blocker
[33]. This was more common in people who were taking
other antihypertensive medications. Hypotension-related Evidence on de‑prescribing alpha‑blockers
adverse events were more common in those on alpha- and centrally acting antihypertensives
blockers than in non-users [33].
The main cardiovascular side effects of the centrally We have been unable to identify any de-prescribing trials
acting antihypertensives are hypotension and orthostatic in older people that focus specifically on alpha-blockers or
hypotension, but both clonidine and moxonidine can cause centrally acting antihypertensives. This situation is balanced,
bradyarrhythmias [34, 35]. to a degree, by the absence of RCT evidence for continuing
these medications in frailer older people. Indeed, the evi-
dence for alpha-blockers is questionable even in non-frail
Neuro‑psychiatric symptoms and sleep groups and lacking for centrally acting antihypertensives.
disorders When considering antihypertensives more generally,
the balance of risks and benefits in physically or cognitive
A number of neuro-psychiatric side effects are listed by the frail older people has been questioned in the research lit-
manufacturers as occurring at a frequency of 0.1–10% in erature for some time [43]. Indeed, there is observational
people treated with both alpha-blockers and centrally act- evidence that the benefits of blood pressure lowering may
ing antihypertensives [34–39]. For alpha-blockers, fatigue is be attenuated and the risks increased in these groups. For
the most common affecting between 5 and 15% of patients instance, the PARTAGE group found an association between
[40]. Sleep disturbance and anxiety can occur with alpha- increased mortality and a systolic BP below 130 mmHg in
blockers, but are reportedly mild [40]. Both fatigue and sleep care home residents taking two or more antihypertensives
disturbance can contribute to falls risk. [44]. The Leiden 85 + study found an association between
Neuro-psychiatric adverse events are more common with cognitive decline and low blood pressure in patients taking
centrally acting antihypertensives. Sedation is common with antihypertensives [45], a finding replicated by Mossello and
both clonidine and methyldopa, occurring in over a third of colleagues [46].
patients [34, 39–41]. Depression is common with clonidine, Regardless of frailty or age, individuals with controlled
and hallucinations and confusion have also been reported blood pressure may no longer require treatment. Van de
although less frequently [34, 41]. Methyldopa is associated Wardt and colleagues review on antihypertensive withdrawal

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European Geriatric Medicine (2023) 14:675–682 679

found that 40% (95% CI 38–42%) of people remained below Preserved ADL Profile)—should undergo detailed frailty/
treatment threshold after antihypertensive medication was functional assessment and tailor antihypertensive therapy
withdrawn at 1 year [47]. Monotherapy and lower blood accordingly, (iii) Older Adults With Significant Loss of
pressure predicted success [47]. Function and Loss of Autonomy for ADL and Limited
Crisafulli and colleagues conducted a systematic review Life Expectancy (Loss of Function and Altered ADL)—
of antihypertensive de-prescribing trials [48]. They identi- The frailest group and the most vulnerable to adverse
fied two open label de-prescribing RCTs—one conducted side effects from treatment [54]. Treatment in this group
in England (OPTIMISE) [49] and the other in the Neth- should be reassessed with symptom relief and quality of
erlands (ECSTATIC) [50], and neither focussed on frail life the primary goal. De-prescribing should be actively
older people. OPTIMISE found that a reduction in antihy- considered.
pertensive medication in community dwellers aged over 80 Primary Health Tasmania produced a guide to de-pre-
was not associated with a significant change in blood pres- scribing antihypertensive agents [55]. The guidance rec-
sure or adverse events during 12 weeks of follow-up [49]. ommends considering dose reduction or cessation of anti-
ECSTATIC found no significant difference in cardiovascular hypertensives in the frail older and/or immobile patient, in
risk over 2 years of follow-up in people aged between 40 those at high risk of falls, and in those with postural hypo-
and 70 (with a low baseline cardiovascular risk) assigned to tension [55]. De-prescribing should be balanced against
either usual care or medication reduction [50]. These studies factors which may favour continuing a medication such
demonstrated that even in non-frail groups, antihyperten- as multiple cardiovascular risk factors or recent stroke.
sives can be de-prescribed effectively. The guideline highlights specific issues with alpha-block-
ers—hypotension, peripheral oedema, worsening of stress
incontinence in women; centrally acting agents—sedation,
Decision aids for de‑prescribing constipation, dry mouth which may prompt a discussion
around de-prescribing [55]. The guideline also highlights
Multiple tools exist to help the clinician identify potentially concerns around possible withdrawal syndromes when
inappropriate medications [51]. Such tools include the medication is discontinued. This could include peripheral
American Geriatric Society Beer’s criteria [32], STOPP/ oedema, tachycardia, rebound hypertension, worsening
START [24], STOPPFall [52] and FORTA [53]. All these heart failure or ischaemic heart disease. On this basis, the
tools highlight centrally acting antihypertensives as poten- guidance recommends dose tapering by 25% every month
tially inappropriate [24, 32, 52, 53]. STOPP/START and [55].
FORTA go further in stating that they should be avoided Scott and colleagues presented a decision framework
in frailer older people with FORTA classifying them as that coalesces around five steps [31]: (i) decide on the ther-
‘D’—“Do not” [24, 53]. Alpha-blockers for hypertension apeutic goals with shared decision-making, (ii) Estimate
are also identified as being potentially inappropriate by all cardiovascular risk and or life expectancy, (iii) Accurately
these tools. FORTA classifying them as ‘C’—“Careful” [53] measure the blood pressure and orthostatic pressures, (iv)
and STOPPFall highlighting them as a medication class of identify threshold and target blood pressures, (v) consider
concern in those at risk of falls [52]. These tools are helpful situations for de-prescribing, e.g. over 80 no cardiovascu-
in assisting the clinician to identify potentially inappropriate lar disease, severe frailty, functional limitations, cognitive
medications but have little to say about how the medica- impairment, history of syncope or falls and life expectancy
tion should be stopped—except STOPPFalls which provides less than 1 year [31].
some guidance [52]. When a decision has been made to de-prescribe, then
We identified four tools to guide the clinician in the prac- a logical, evidence-based approach to medication with-
ticalities of prescribing/de-prescribing antihypertensives in drawal is needed. Harrison and colleagues conducted a
older frailer people. Two developed in Australia and two in review of the literature, guidelines and British National
Europe. Formulary (BNF) to develop an antihypertensive with-
Benetos and colleagues advocate stratifying antihyper- drawal procedure and monitoring procedure [56]. This
tensive treatment according to frailty and functional status formed part of a broader study examining the feasibility
[54]. Their objective was to avoid exclusion based solely of withdrawing antihypertensive medication in people with
on advanced age and to avoid aggressive therapy target- dementia and well-controlled hypertension [57]. However,
ing only life prolongation. They identify three groups: (i) it does have potentially wider applications. This protocol
Older adults with preserved functional status (Preserved provides an evidence-based tool for clinicians to use as an
Function Profile)—consider full therapy, (ii) Older adults aid to the practical aspects of dose reduction, treatment
with moderate functional decline and preserved autonomy withdrawal and monitoring [56].
for activities of daily living (ADL) (Loss Of Function/

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680 European Geriatric Medicine (2023) 14:675–682

Fig. 1  Alpha-blocker and

centrally acting antihypertensive
de-prescribing algorithm

Conclusions • Assess frailty and function—Consider more detailed

assessment using an approach like comprehensive geri-
Hypertension is one of the commonest long-term health atric assessment.
conditions. Multiple studies have shown reductions in • Consider contraindications—Are there any concerning
morbidity and mortality with appropriate antihypertensive symptoms or signs, e.g. syncope, bradyarrhythmias, heart
treatment. Alpha-blockers and, to a lesser extent, centrally failure? De-prescribe if a clear contraindication is pre-
acting antihypertensives still form a sufficient component sent.
of the therapeutic treatments for high blood pressure that • Assess side effects—Consider non-cardiovascular side
the clinician will encounter them routinely. However, the effects, such as sedation, depression, etc.
evidence of benefit, in terms of morbidity and mortality, • Deprescribing—Slow reduction to avoid withdrawal syn-
is poorer for these groups than any other antihypertensive, drome. Monitor blood pressure.
and these classes of antihypertensives are of particular
concern when it comes to the frailer patient who is at risk
of falls. Multiple tools flag these medications as poten-
tially inappropriate for frail older people, and a number of Future perspectives
guidelines exist which can aid the clinician to review, and
safely and appropriately de-prescribe. Many clinicians are still hesitant when it comes to de-pre-
In summary, some advice can be offered to the clini- scribing. Concerns about withdrawal syndromes and patient
cian managing a patient at risk of falls who is prescribed beliefs about the need to continue blood pressure medica-
an alpha-blocker or centrally acting antihypertensive for tions indefinitely are often cited as issues. Future research
high blood pressure: should examine how clinicians and patients can be helped
and supported to de-prescribe safely and appropriately.
• Centrally acting antihypertensives and alpha-blockers
should be prioritised for de-prescribing in any older
Author contributions Tomas Welsh performed the literature search,
frailer individual at risk of falls unless there is an over- screening, data analysis and drafted the work for publication. Anneka
whelming indication for them to continue. Mitchell reviewed and critically revised the manuscript.
• Algorithm—We present a de-prescribing algorithm
(Fig. 1). Declarations
• Shared decision-making—Individualise treatment and
Conflict of interest The authors have no relevant financial or non-fi-
treatment goals, whenever possible, guided by patient nancial interests to disclose. No funding was received for conducting
priorities, symptoms, and individual risk profiles. this study.
• Confirm the diagnosis—Look for orthostatic hypoten-
sion—measure postural blood pressures, then look Ethical approval This study does not contain any studies with human
participants performed by any of the authors.
again.

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European Geriatric Medicine (2023) 14:675–682 681

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guida​nce/​cg127/​evide​nce/​cg127-​hyper ​tensi​on-​full-​guide​line3.
included in the article's Creative Commons licence, unless indicated
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