Expert Opinion on Pharmacotherapy

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Pharmacological management of malignant

hypertension

Joanna Lewek, Agata Bielecka-Dąbrowa, Marek Maciejewski & Maciej

Banach

To cite this article: Joanna Lewek, Agata Bielecka-Dąbrowa, Marek Maciejewski & Maciej
Banach (2020): Pharmacological management of malignant hypertension, Expert Opinion on
Pharmacotherapy, DOI: 10.1080/14656566.2020.1732923

To link to this article: https://doi.org/10.1080/14656566.2020.1732923

Published online: 26 Feb 2020.

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EXPERT OPINION ON PHARMACOTHERAPY
https://doi.org/10.1080/14656566.2020.1732923

SPECIAL REPORT

Pharmacological management of malignant hypertension

Joanna Leweka,b, Agata Bielecka-Dąbrowaa,c, Marek Maciejewskib and Maciej Banacha,d,e
a
Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Lodz, Poland; bDepartment of Cardiology and
Adult Congenital Heart Diseases, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland; cHeart Failure Unit, Department of Cardiology
and Adult Congenital Heart Diseases, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland; dPolish Mother’s Memorial Hospital
Research Institute, Lodz, Poland; eCardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland

ABSTRACT ARTICLE HISTORY

Introduction: According to current guidelines, malignant hypertension is one of the emergencies in Received 14 November 2019
hypertension. The definition requires the presence of bilateral retinal hemorrhages or exudates, with or Accepted 18 February 2020
without papilledema, acute heart failure and acute deterioration in renal function in severe hyperten- KEYWORDS
sion. Patients with malignant hypertension are characterized by pronounced target organ damage, Labetalol; malignant
including structural and functional cardiac abnormalities and renal insufficiency. hypertension; nicardipine;
Areas covered: Knowledge of the available treatment options is extremely important as we know that we only nitroprusside;
have a limited time to reduce blood pressure. There are only four drugs dedicated to immediate blood pressure pharmacotherapy; urapidil
lowering in patients with malignant hypertension, including ‘first-line’ and alternative drugs. Our review aims to
discuss all those drugs and gives practical suggestions on how to properly use them.
Expert commentary: The decision of which drug to use depends on numerous factors including the clinical
indications, pharmacokinetics, toxicity and drug interactions. Furthermore, frequently, more than one of the
recommended drugs is required for the successful lowering of the patient’s blood pressure.

1. Introduction includes other ischemic target organ damage (funduscopic

Hypertension serves as a risk factor for cardiovascular diseases.
One of its severe forms is malignant hypertension. Current
European Society of Cardiology (ESC) and the European
Society of Hypertension (ESH) guidelines [1] enlist malignant
hypertension (MHT) as an urgency and emergency emphasiz-
ing that it is severe (most often grade 3 hypertension) and has
poor prognosis if untreated [2–5]. Over the last decades, there
have been many controversies over the definition of MHT. The
traditional understanding of the term ‘malignant hyperten-
sion’ means that hypertension is severe and is accompanied
by funduscopic changes including retinal flame hemorrhages,
exudates, spots sometimes with papilledema. The first objec-
tion to that definition is that it does not offer exact values of
blood pressure (BP) from which MHT should be diagnosed.
Amongst some of the values present in different papers, there
is 150 mmHg of mean arterial pressure [6] and 130 mmHg of
diastolic BP [7]. Another objection is that the definition
includes only one target organ damage, which probably cor-
responds to the fact that when it was created there were no
other techniques for assessment of other organ damage.
Nowadays, it seems that it should be expanded because
other organ damage can be easily diagnosed [8,9]. Moreover,
ischemic lesions may appear earlier in other organs, so diag-
nosis should not be delayed. The controversies over MHT
definition has resulted in new proposals to requalify it to
hypertension-MOD (multi organ damage) [3,10].The ESC/ESH
guidelines now present an expanded definition which
changes including papilledema or flame hemorrhages, micro-
angiopathy, disseminated intravascular coagulation, encepha-
lopathy, acute heart failure and acute deterioration in renal
function) [1]. The guidelines devote a particularly small
amount of space to MHT. Even that reflects that the topic of
malignant hypertension is not fully understood and that it
needs further studies which is rather difficult taking into
account it’s prevalence and the need for rapid management.
2. Treatment of malignant hypertension
According to the guidelines, we have limited hours to reduce mean
blood pressure by 20 to 25%. Drugs dedicated to immediate BP
lowering can be divided into first-line (Labetalol and Nicardipine)
and alternative (Nitroprusside and Urapidil) [1] and should be
administered in hospital. However, not all these drugs are readily
available in many countries; consequently, other options may
include non-dihydropyridine calcium channel blockers (diltiazem),
beta-blockers (metoprolol, esmolol), angiotensin converting
enzyme (enalapril) and central alpha-agonists (clonidine).
Although intravenous drugs are recommended for most hyperten-
sive emergencies, oral therapy with angiotensin converting enzyme
(ACE) inhibitors, ARBs (angiotensin receptor blockers) and beta-
blockers is also very effective in malignant hypertension [1].
However, low initial doses should be used because these patients
can be very sensitive to these agents and treatment should take
place in hospital.

CONTACT Joanna Lewek joanna.lewek@umed.lodz.pl Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz,
Lodz, Poland
© 2020 Informa UK Limited, trading as Taylor & Francis Group
2 J. LEWEK ET AL.
Article highlights
● In malignant hypertension, there is only a limited time to reduce
blood pressure
● Drugs dedicated to immediate BP lowering can be divided into first-
line (Labetalol and Nicardipine) and alternative (Nitroprusside and
Urapidil)
● Various studies have been conducted over new drugs using animal
models: examples include fenofibrate and the 20-HETE receptor
antagonist (AAA) with new mechanisms of action
● Combination therapy seems to be crucial in effective blood pressure
lowering
● There is a general lack of studies on the treatment of malignant
hypertension due to its rare prevalence and sudden characterization
This box summarizes key points contained in the article.
Our review aims to to discuss the current pharmacotherapy
for malignant hypertension. The topic remains significant
despite the fact that the prevalence of MHT is low in the
general population.
2.1. Labetalol
Labetalol is selective for alpha1 adrenergic blocker and is
nonselective for betaadrenergic receptors, and a competitive
blocker of alpha1, beta1 and beta2 receptors [11]. Clinical
practice shows that labetalol is indicated in a few conditions
including severe hypertension during pregnancy, acute
ischemic stroke and intracranial hemorrhage. What is more, it
is also indicated for acute hypertensive events with an initial
prescribed dosage of 20 mg iv over 2 minutes, then continua-
tion with 40 to 80 mg iv for 10 minutes. The total dose should
not exceed 300 mg per day [11]. Another option is continuous
iv infusion and such an alternative sees the use of 1 to 2 mg/
min with the potential of titrating up to 10 mg per minute
[11]. There are no studies over modifications of dosing in
patients with renal and hepatic impairment.
2.2. Nicardipine
Nicardipine is a calcium channel blocker which can be used in
malignant hypertension. It acts through dilatation of arterioles,
thus reducing the total peripheral resistance as well as the
afterload [12]. Nicardipine should not be used in patients
suffering from advanced aortic valve stenosis because it
reduces the afterload. The initial dosage is 5 mg/hour iv infu-
sion and can be increased by 2.5 mg/hour every 5 − 15 minutes.
Maximal dosage is 15 mg/hour [12]. The other calcium channel
blockers are also sometimes used in malignant hypertension.
However, it should be emphasized that their role can be
decreased by common related edema [12].
2.3. Nitroprusside sodium
Nitroprusside sodium is a vasodilator acting on arteries and
veins. It is indicated for the immediate reduction of blood
pressure [13,14]. The initial dose of nitroprusside sodium is
0.3 mcg/kg/min and may be titrated upward to 10 mcg/kg/
min [1]. The drug starts acting within a minute after the start
of its infusion and lasts till the end of infusion. What is more, it
is unstable when exposed to light and the period of adminis-
tration needs to be short in order to avoid cyanide intoxication
[14]. Importantly, what should be emphasized is that nitro-
prusside sodium should not be used in cases of compensatory
hypertension in patients with aortic coarctation or atriovenous
shunts [14].
2.4. Urapidil
Urapidil is an antiadrenergic drug that acts through the dilata-
tion of arterioles and thus reduces the total peripheral resis-
tance [15]. It is dedicated to hypertensive emergencies. The
initial dosage is 10 to 50 m and it should be slowly injected.
Blood lowering is expected within 5 min. Next doses can be
repeated if necessary. Continuous infusion is used to maintain
an achieved level of blood pressure. The infusion rate depends
on the individual patient with the initial infusion rate being
2 mg/min. The maintenance dose is on average 9 mg/hour.
The duration of the treatment should not exceed 7 days
because, from toxicological point of view, it seems to be
safe. Similarly to nicardipine, urapidil should not be used in
patients with aortic valve stenosis and additionally with an
atriovenous shunt [15].
The above discussed list of drugs recommended in the
most severe form of hypertension is quite short. Additionally,
their use is sometimes decreased by availability, contraindica-
tions or effectiveness. Therefore, recent studies have tried to
search for new substances which could be useful also in
malignant hypertension.
2.5. The potential new options in the treatment of
malignant hypertension
The first studied drug is well-known but in a different group of
patients [16]. Fenofibrate, one of the lipid-lowering drugs, has
appeared to be effective in rats in which malignant hyperten-
sion was induced by the activation of a mouse renin gene by
a natural xenobiotic indole-3-carbinol. In that experimental
setting, fenofibrate lead to the suppression of renin-
angiotensin system activity (suppression of renin gene expres-
sion, a reduction in plasma renin activity, and a reduction in
plasma and kidney angiotensin II levels) [17]. However, there is
no information whatsoever that the drug could be useful in
human malignant hypertension. The hypothesis of this animal
study was based on the fact that fenofibrate can increase the
renal production of 20-hydroxyeicosatetraenoic acid (20-HETE)
which is a product of the cytochrome P450 (CYP)-dependent
ω-hydroxylase pathway [17]. Furthermore, 20-HETE, which is
a tubular transport inhibitor, strengthens sodium excretion
and prevents the development of Angiotensin II-dependent
MHT. Fenofibrate led to the suppression of the activity of the
renin-angiotensin system [17].
Likewise, there was a study conducted in transgenic rats
with a new 20-HETE receptor antagonist (AAA) [18]. Induction
of malignant hypertension in transgenic rats was performed
through the use of indole-3-carbinol [18]. The use of AAA in
rats with malignant hypertension led to systolic blood pressure

reduction, decreased albuminuria, glomerulosclerosis index and
cardiac hypertrophy; it also attenuated the development of
malignant hypertension probably due to suppression of the
intrarenal angiotensin II. The new drug AAA has not been
studied in humans yet.
Furthermore, recent studies have shown the effectiveness
of well-known antihypertensive drugs valsartan and eplere-
none in the treatment of malignant hypertension [19,20].
However, it is worth emphasizing that those drugs were
used as combination therapies with other antihypertensive
drugs [19,20], so there is no compelling evidence that they
will work in an individual setting.
3. Conclusion
Malignant hypertension as the most severe form of hyperten-
sion should be quickly and effectively treated. According to
current guidelines, we have several options of treatment:
Labetalol and Nicardipine, which serve as first-line drugs and
Nitroprusside and Urapidil as alternative drugs. There are stu-
dies on new drugs that block the 20-HETE receptor – the
results of which are promising but have only demonstrated
activity in animal models. Other treatment options include
combination therapy with well-known antihypertensive drugs.
4. Expert opinion
Despite the fact that malignant hypertension is a hypertensive
emergency that should be effectively treated, the current ESC/
ESH guidelines provide insufficient guidelines for it. We know
that it requires immediate treatment with intravenous drugs.
Among possible treatment options, we have only four intra-
venous fast-acting drugs. Those drugs are divided into first-
line and alternative. Little attention has been given to the
decision-making process in terms of which of these drugs
should be used first. From our point of view, the decision of
which drug is used must be based on many factors including
the clinical indications, pharmacokinetics, toxicity and drug
interactions. What is more, frequently, more than one of
those drugs is necessary to successfully lower blood pressure.
It is worth emphasizing that there are no precise guidelines on
how to manage malignant hypertension but it should be done
carefully, under close supervision with a gradual reduction in
blood pressure, and with the ability to back down if target
organ function deteriorates. Furthermore, there is a general
lack of new studies on the four drugs mentioned in the ESC/
ESC guidelines. Recent papers have focused on animal studies
of new drugs which use new pathomechanisms and on the
possibility of combination therapy. Of course, the sudden
character of the disease and its rare prevalence makes things
more problematical. As such, it would be difficult to plan
randomized trial, and we often only have observational stu-
dies. This is why the new studies on animals are most promis-
ing. Indeed, the biggest challenge with malignant
hypertension is to better understand the pathomechanism of
malignant hypertension, which could result in more effective
treatment. The forthcoming years may bring about new treat-
ment options which were previously studied in animals.
Another important issue concerns the controversy over the
EXPERT OPINION ON PHARMACOTHERAPY 3
definition of malignant hypertension and, certainly, a universal
definition is necessary and it should include organ damage
beyond simply retinopathy. The authors firmly believe that
a universal definition would only benefit the planning of
scientific activities. Overall, we need to develop the therapeu-
tic options available for malignant hypertension as the most
severe cases are sometimes difficult to treat. We also need to
confirm the current therapeutic options available.
Funding
This manuscript has not been funded.
Declaration of Interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Williams B, Mancia G, Spiering W, et al. ESC/ESH Guidelines for the
management of arterial hypertension. Eur Heart J.
2018;39:3021–3104.
•• The guidelines are the only recommendation of how to treat
patients with malignant hypertension.
2. van den Born BJ, Koopmans RP, Groeneveld JO, et al. Ethnic
disparities in the incidence, presentation and complications of
malignant hypertension. J Hypertens. 2006;24:2299–2304.
3. Cremer A, Amraoui F, Lip GY, et al. From malignant hypertension to
hypertension-MOD: a modern definition for an old but still danger-
ous emergency. J Hum Hypertens. 2016;30:463–466.
4. Ginna G, Pascale C, Fornengo P, et al. Hospital admissions for
hypertensive crisis in the emergency departments: a large multi-
centre Italian study. PLoS One. 2014;9:e93542.
5. van den Born BJ, Lowenberg EC, van der Hoeven NV, et al.
Endothelial dysfunction, platelet activation, thrombogenesis and
fibrinolysis in patients with hypertensive crisis. J Hypertens.
2011;29:922–927.
6. van den Born BJ, Beutler JJ, Gaillard CA, et al. Dutch guideline for
the management of hypertensive crisis – 2010 revision. Neth J Med.
2011;69:248–255.
7. Januszewicz A, Guzik T, Prejbisz A, et al. Malignant hypertension:
new aspects of an old clinical entity. Pol Arch Med Wewn.
2016;126:86–93.
8. Bielecka-Dabrowa A, Aronow WS, Rysz J, et al. The rise and fall of
hypertension: lessons learned from Eastern Europe. Curr Cardiovasc
Risk Rep. 2011;5:174–179.
9. Bielecka-Dabrowa A, Michalska-Kasiczak M, Gluba A, et al.
Biomarkers and echocardiographic predictors of myocardial dys-
function in patients with hypertension. Sci Rep. 2015;5:8916.
10. Shantsila A, Gregory YH. Malignant hypertension not quite an
obsolete diagnosis yet. J Hypertens. 2019;37:282–283.
11. MacCarthy EP, Bloomfield SS. Labetalol: a review of its pharmacol-
ogy, pharmacokinetics, clinical uses and adverse effects.
Pharmacotherapy. 1983;3:193–219.
4 J. LEWEK ET AL.
12. Wallin JD, Fletcher E, Ram CVS, et al. Intravenous nicardipine for the
treatment of severe hypertension: a double-blind, placebo-controlled
multicenter trial. Arch Intern Med. 1989;149:2662–2669.
13. Friederich JA, Butterworth JF. Sodium nitroprusside: twenty years
and counting. Anesth Analg. 1995;81:152–162.
14. Robin ED, McCauley R. Nitroprusside-related cyanide poisoning:
time (long, past due, for urgent, effective interventions. Chest.
1992;102:1842–1845.
15. Bottorff MB, Hoon TJ, Rodman JH, et al. Pharmacokinetics and
pharmacodynamics of urapidil in severe hypertension. J Clin
Pharmacol. 1988;28:420–426.
16. Sahebkar A, Simental-Mendía LE, Katsiki N, et al. Effect of fenofi-
brate on plasma apolipoprotein C-III levels: a systematic review and
meta-analysis of randomised placebo-controlled trials. BMJ Open.
2019;8:e021508.
17. Jichova S, Dolexelova S, Kopkan L, et al. Fenofibrate attenuates
malignant hypertension by suppression of the Renin-angiotensin
system: a study in Cyp 1a1-Ren-2-Trarnsgenic Rats. Am J Med Sci.
2016;352:618–630.
• This is a new animal study assessing new drugs and patome-
chanism of malignant hypertension.
18. Sedlakova L, Kikerlova S, Huskova A. 20-Hydroxyeicosatetraenoic
acid antagonist attenuates the development of malignant hyper-
tension and reverses it once established: a study in Cyp1a1-Ren-2
transgenic rats. Biosci Rep. 2018;12:pii.
• This is a new animal study assessing new drugs and patome-
chanism of malignant hypertension.
19. Michaud CJ, Trethowan B. Valsartan effective for malignant hyper-
tension after aortic dissection with renal artery involvement.
Pharmacotherapy. 2018;38:e25–e28.
20. Takahashi F, Goto M, Wada Y, et al. Successful treatment with an
antihypertensive drug regimen including eplerenone in a patient
with malignant phase hypertension with renal failure. Intern Med.
2015;54:2467–2470.