URAPIDIL

High Blood Pressure in Adults

Trattamento dell’ipertensione

• Trattamento non farmacologico

• Trattamento farmacologico
Trattamento non farmacologico
• DIETA:
o Ridurre l’assunzione di sodio;
o Seguire una dieta ad alto contenuto di verdure,
frutta secca, cereali, pesce, pollame e a basso
contenuto di dolci, carni rosse e bevande
zuccherate;

• ATTIVITÀ FISICA: impegnarsi in tre o quattro

sessioni da 40 minuti a settimana di attività fisica
aerobica moderata-intensa
 Trattamento farmacologico
• Farmaci di prima linea per l’ipertensione:
o Calcioantagonisti
o Modulatori del sistema renina-angiotensina:
 ACE-inibitori
 Bloccanti dei recettori dell’angiotensina
 Inibitori diretti della renina
o Diuretici
• Farmaci aggiuntivi per l’ipertensione difficile da trattare:
o Antagonisti del recettore dei mineralcorticoidi e
antagonisti di ENaC
o β-bloccanti
o α-bloccanti
o Simpaticolitici centrali (es. α-metildopa)
o Vasodilatatori diretti (Minoxidil, Idralazina)
α-bloccanti
 Alpha-1-adrenoreceptor antagonists
(alpha-blockers) have been shown to
have a BP-lowering effect broadly
similar to the other antihypertensive
drug classes.

Heran BS, Galm BP, Wright JM. Blood pressure lowering efficacy of alpha blockers for primary
hypertension. Cochrane Database Syst
Rev. 2009;4:CD004643.
 Several studies have indicated
that alpha-blocker add-on
therapy is effective in reducing
BP in patients with
inadequately controlled
hypertension.
Zusman RM. The role of alpha 1-blockers in combination therapy for hypertension. Int J Clin
Pract. 2000;54:36-40.
 Alphablockers may also have
therapeutic benefits that go beyond BP
control, including improvements in
lipid profile and glucose
metabolism, as well as reducing the
symptoms of benign prostatic
hyperplasia (BPH).

Zusman RM. The role of alpha 1-blockers in combination therapy for hypertension. Int J Clin
Pract. 2000;54:36-40.
URAPIDIL
 FARMACOCINETICA (1)
Following intravenous administration of 25 mg of
urapidil, a biphasic pattern of its concentration in
the blood is observed (initial distribution phase,
final phase of elimination).

The distribution phase has a half-life of about 35 minutes.

The volume of distribution is 0.8 (0.6-1.2) l / kg.

 FARMACOCINETICA (2)
Urapidil is mainly metabolised in the liver.

The main metabolite is urapidyl hydroxylated

in position 4 of the phenyl ring, which does not
possess an appreciable antihypertensive
activity.

The urapidyl O-demethylate metabolite has

approximately the same biological activity as
urapidil, but is present only in small amounts.
 FARMACOCINETICA (3)
The elimination of urapidil and its
metabolites in humans is up to 50-70%
renal;
of which 15% of the administered dose is
pharmacologically active urapidil; the
remainder, mainly consisting of urapidil
para-hydroxylate without antihypertensive
activity, is excreted via the faecal route.
 FARMACOCINETICA (4)
The serum half-life after intravenous bolus
administration is 2.7 h (1.8-3.9 h).
The binding of urapidil with plasma proteins, in human
serum, in vitro is equal to 80%.
This relatively low binding affinity of urapidil with plasma proteins
could explain why no interactions between urapidil and medicinal
products with a strong plasma protein binding are known.
In elderly patients and in patients with marked hepatic and / or renal impairment,
the volume of distribution and clearance of urapidil are reduced and the plasma half-
life is longer.

Urapidil crosses the blood-brain barrier and passes the placenta.

L’emivita sierica dopo somministrazione in bolo endovenoso è 2,7 h (1,8-3,9 h).
 FARMACODINAMICA
Urapidil ha effetti sia centrali che periferici.
Urapidil has been shown to have a dual action:
firstly it works as a selective α1-
adrenoreceptor antagonist and secondly as an
agonist of 5-HT1A receptors in the central
nervous system.
 EFFETTI PERIFERICI
The α1-adrenergic receptor blocking action of
urapidil causes a reduction of vascular tone,
thus promoting both arterial and venous
vasodilatation in the systemic and the
pulmonary circulation sleading to a
reduced systemic and pulmonary arterial
resistance, resulting ultimately in a
decreased blood pressure.

Valenta, B.,Kotai,E.,Weisz,E.,Singer,E.A.,1990.Influence of urapidil and 8-OH- DPAT on brain5 HT

turnover and blood pressure in rats.J.Cardiol.Pharm.15, S68–S74.
 The peripheral α1 adrenoceptor
blockade has been suggested as the
major effect contributing to the
antihypertensive action of urapidil.
Saxena,P.R.,Villalon,C.M.,1990.5-HT1A receptor Agonism: a novel mechanism for
Antihypertensive action. Trends Pharmacol.Sci.11,95–96.

Gross, G.,Hanft,G.,Rugevics,C.,1987.5-methyl-urapidil discriminates between subtypes of the

α1-Adrenoceptor.Eur.J.Pharmacol.151,333.

Van Zwieten,P.A.,Blauw,G.J.,VanBrummelen,P.,1990.Pharmacological profile of

Antihypertensive drugs with serotonin receptor and α1-Adrenoceptoractivity.
Drugs 40,1–8.
Grohs, J.G.,Huber,S.,Fischer,G.,Raberger,G.,1992.Influence of α1-Adrenoceptor
Blockade and/or 5-HT1A Agonism on blood pressure and heart rate at rest during exercise in
hypertensive dogs.J.Auton.Pharmacol.12(3),157–164.
 EFFETTI CENTRALI

In addition,
Urapidil has also been shown to reduce blood
pressure by activating 5-HT1A receptors in the
ventromedullary region of the brain.

However, the possibility that urapidil might also activate 5HT1A

receptors localized in peripheral blood vessels to reduce vascular tone
remains to be assessed.
Serotonin has been shown to induce endothelium-dependent
relaxation of several types of isolated blood vessels
such as the porcine coronary artery (Vanhoutte, 1998), the porcine
pulmonary artery (Glusa andRoos,1996; RoosandGlusa,1998), and the
human pulmonary artery (Despoix et al.,2009).
 EFFETTI METABOLICI
Effect of Urapidil in Patients
with Type 2 Diabetes and Hyperlipidemia
 Influence of a new multifactorial antihypertensive on blood pressure
and metabolic profile in essential hypertension associated with non-
insulin-dependent diabetes mellitus.
Fariello R, Boni E, Corda L, Zaninelli A, Noseda A, Spinazzi A. Eur Heart J. 1992;13(suppl. A):65-69.

In a large randomized study of urapidil, 309 patients with type 2 diabetes and mild to moderate
hypertension were treated with urapidil at a dose of either 60 mg/day (n=157) or 120 mg/day
(n=152) for 4 weeks. BP was significantly reduced (P<0.01) in both treatment groups at 4
and 16 weeks. Fasting blood glucose and glycated hemoglobin (HbA1c) decreased
significantly (P<0.01) during treatment with both urapidil 60 mg and 120 mg/day
(Figure 2). No further changes were seen with the addition of thiazide.

Treatment with urapidil was also associated with a significant decrease in total
cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides, and a
significant increase in highdensity lipoprotein (HDL) cholesterol.
This lipid-lowering effect was dose related, with the reduction in triglycerides significantly
greater in patients treated with the higher dose.
When thiazide was added to nonresponders to urapidil, there was a significant increase in
total cholesterol and a significant decrease in HDL cholesterol.
 Efficacy and tolerability of slow release urapidil (ebrantil) in
hypertensive patients with non-insulin dependent diabetes mellitus
(NIDDM).
Oren S, Turkot S, Paran E, Flandra O, Slezak L, Hof B. J Hum Hypertens. 1996;10:123-127.

In another study, 33 patients with type 2 diabetes and DBP of 95-115 mmHg were treated
with either 60 or 120 mg/day of urapidil, with a gradual increment up to a maximum of
180 mg/day in order to reduce DBP to <90 mmHg or by at least 10% in the sitting position.
Significant reductions (P<0.0001) in sitting and standing SBP and DBP were achieved
after 12 weeks of treatment, whereas heart rate did not increase. Unlike in the study by Fariello
et al, HbA1c levels were not improved with urapidil.
Fasting insulin levels before a standard oral glucose tolerance test were similar at baseline and
after 12 weeks of treatment, but peak concentration at 90 minutes after glucose loading was
higher at study end. The ratio of insulin to glucose (used as an indirect marker of insulin
resistance) was significantly lower after treatment with urapidil 60-180 mg.
This suggests that urapidil increased insulin sensitivity, since
patients treated with urapidil needed less endogenous insulin in order
to maintain similar blood glucose levels.
Altri effetti di Urapidil…
 Urapidil treatment decreases plasma fibrinogen
concentration in essential hypertension.

Metabolism. Haenni A, Lithell H. 1996;45:1221-1229.

In a study in which 42 patients with hypertension were randomized to double-blind

treatment with urapidil 120 mg/day or atenolol 50 mg/day, urapidil had a
beneficial effect on plasma fibrinogen level, which decreased by 24%
after 12 weeks with urapidil compared with a 9% decrease with atenolol 50 mg.29
Plasminogen activator inhibitor activity decreased by 4% in the urapidil group and
increased by 17% in the atenolol group, although this difference was not significant.
 Fibrinogen as a cardiovascular risk factor: a meta-analysis
and review of the literature.
Ernst E, Resch KL. Ann Intern Med. 1993;118:956-963.

Plasma fibrinogen level and the risk of major cardiovascular

diseases and nonvascular mortality: an individual
participant meta-analysis.
Danesh J, Lewington S, Thompson SG, et al. JAMA. 2005;294:1799- 1809.

Previous studies have suggested a correlation

between plasma fibrinogen and subsequent
myocardial infarction or stroke.
 Acute effect of urapidil on peripheral serotonin metabolism.
Sebeková K, Fedelesová V, Blazícek P, Dzúrik R. Cor Vasa. 1990;32:274-281.

Platelet in vitro responses to urapidil and prazosin.

Smith CC, Betteridge DJ, Prichard BN. Drugs. 1990;40(suppl. 4):48-51.

Effects of urapidil on 5-hydroxytryptamine induced platelet

aggregation and on 14C-5 hydroxytryptamine uptake in platelets.
Storck J, Ochs JG, Kirsten R. Int J Clin Pharmacol Ther
Toxicol. 1990;28:303-308.

Several studies have shown a dose dependent inhibitory effect of

urapidil on platelet aggregation in vitro, in volunteers and in
patients with hypertension.

However, the clinical relevance of these findings is

uncertain.
 Adverse events
Adverse events in clinical trials tended to be mild, and transient,
mostly occurring in the first week of therapy and subsiding with
continued treatment.
These included:
• Dizziness
• Nausea
• Headaches
• Fatigue
• Orthostatic disorders
Compared with other antihypertensive agents, the incidence of adverse events with
urapidil is generally similar.
However, because of its dual mode of action, urapidil may have a
lower incidence of tachycardia and orthostatic hypertension
compared with other alphablockers.
 Therapeutic Effects
with Intravenous Administration
• Hypertensive Crises

• Stroke and Intracerebral Hemorrhage

• Pre-eclampsia and Eclampsia

• Perioperative Hypertension: Prevention of hypertensive episodes

in patients undergoing preparation for surgery of
pheochromocytoma
Hypertensive crisis
 Hypertensive Crises
Intravenous administration of urapidil results in a rapid
antihypertensive effect within 2 minutes
and
is not associated with reflex tachycardia,

which means it may be a useful treatment

option for hypertensive crises.
Intravenous urapidil versus sublingual nifedipine in the
treatment of hypertensive urgencies.
Hirschl MM, Seidler D, Zeiner A, et al. Am J Emerg Med. 1993;11:653-656.

In a prospective study in an outpatient population, intravenous urapidil was compared with

sublingual nifedipine for the treatment of hypertensive urgencies (BP >200/110 mmHg).

Response to treatment was defined as a stable reduction of BP below 180/100

mmHg 15 minutes after application of a single dose of either intravenous
urapidil 25 mg (n=26) or sublingual nifedipine 10 mg (n=27).
If required, patients received a second dose of urapidil 12.5 mg or nifedipine 10 mg.

After a single dose, response rate was 92%

in the urapidil group compared with 70% in
the nifedipine group.
 Stroke and Intracerebral Hemorrhage
Although no studies have specifically investigated the efficacy of urapidil in stroke
management, there is some evidence to suggest that urapidil has properties that may be
useful in the treatment of acute stroke.

Potential beneficial effects of urapidil in primary and secondary prevention of stroke.

Späh F, Walsemann SO. Blood Press Suppl. 1995;3:62-67.

BP reduction with urapidil is generally not associated with an increase in intracranial pressure
and cerebral perfusion pressure is not affected.

Urapidil has also been shown to have a potential protective effect against ischemia, with
neuroprotective effects being shown in rodents.

Neuroprotective properties of 5-HT1A receptor agonists in rodent models of focal and global cerebral
ischemia.
Prehn JH, Backhauss C, Karkoutly C, et al. Eur J Pharmacol. 1991;203:213- 222.

Intravenous urapidil is one of the agents recommended in European guidelines for lowering
blood pressure in the management of acute stroke.
 Stroke Coding
Guide of the American Academy of Neurology
Algorithm for emergency treatment of blood pressure in patients with ischemic stroke.
1. The automatic sphygmomanometer should be checked against one of a kind manual.
2. If the diastolic pressure values, in two successive measurements after 5 minutes, exceed 140 mm Hg, start the continuous infusion e.v. of
an antihypertensive agent such as nitroglycerin or sodium nitroprusside (0.5-1.0 mg / kg / min), of which, however, it goes the risk of
cerebral edema, especially in large, is carefully monitored heart attacks, given their ability to increase intracranial pressure. Patients with
these findings are not candidates for thrombolytic treatment with t-PA.
3. If the systolic blood pressure values ​are> 220 mm Hg, or the diastolic pressure is between 121- 140 mm Hg, or the
mean arterial pressure is> 130 mm Hg in two measurements after 20 minutes, administer an antihypertensive drug
easily dosable as labetalol, 10 mg e.v. in 1-2 minutes. This dose can be repeated or doubled every 10-20 minutes up
to a cumulative dose of 300 mg. Following this initial approach, labetalol can be administered each 6-8 hours if
necessary. Labetalol is not recommended for patients with asthma, heart failure or severe illness of the conduction.
In these cases urapidil (10-50 mg in bolus, ie infusion 0.15-0.5 mg / min). Patients requiring more than two doses of
labetalol or other antihypertensive drugs to reduce systolic blood pressure <185 mm Hg o diastolic <110 mm Hg, are
not generally candidates for thrombolytic therapy.
4. If the systolic pressure value is 185-220 mm Hg or diastolic of 105-120 mm Hg, emergency therapy should be postponed if one does not
coexist left ventricular failure, aortic dissection or a myocardial infarction acute. Patients who are candidates for t-PA therapy who have
persistent values high pressures, systolic> 185 mm Hg or diastolic> 110 mm Hg, can be treated with small doses of antihypertensive e.v. to
keep the PA values ​just below these limits. However the administration of more than two doses of antihypertensive to keep under PA
control is a contraindication related to thrombolytic therapy.
5. The use of calcium antagonists by sublingual route is not indicated for risky rapidity of action of this type of administration.
6. Correction of arterial pressure by antihypertensive agents in the acute phase of stroke should be associated with careful monitoring of the
state neurological to promptly detect the appearance of deterioration.
7. In patients with acute ischemic stroke and systolic pressure <185 mm Hg or diastolic <105 mm Hg, antihypertensive therapy is not usually
indicated.
8. Although there are no data to define a threshold for the treatment of hypotension arterial in patients with acute stroke, this is
recommended in case of signs of dehydration and / or pressure values ​significantly lower than the usual ones for the patient data.
Therapeutic options include the administration of fluids e.v., the treatment of congestive heart failure and bradycardia, ed possibly
vasopressor agents such as dopamine.
Perioperative Hypertension
Intravenous urapidil has also been shown to be effective in the management of
perioperative hypertensive episodes in patients undergoing a variety of surgical operations:

• Prevention of hypertensive episodes in patients

undergoing preparation for surgery of
pheochromocytoma
Preparation for surgery of phaeochromocytoma by blockade of alphaadrenergic receptors with urapidil: what dose?
Gosse P, Tauzin-Fin P, Sesay MB, Sautereau A, Ballanger P. J Hum Hypertens. 2009;23:605-609.

• Coronary artery surgery

• Abdominal aorta surgery
• Neurosurgery
• Tracheal intubation under general anesthesia