PHARMACOTHERAPY OF HYPERTENSIVE EMERGENCY.pptx

PHARMACOTHERAPY OF
HYPERTENSIVE EMERGENCY:
HYDRALAZINE AND LABETATOL
DR ANTHONY KWAW, RESIDENT PHARMACIST
ACCIDENT AND EMERGENCY
TAMALE TEACHING HOSPITAL
TAMALE, GHANA
Email: kwawanthony7@gmail.com
1
DR ANTHONY KWAW (RESIDENT PHARMACIST), A&E, TTH

OUTLINE
• Introduction
• Epidemiology
• Pathophysiology
• Signs and symptoms
• Pharmacological management
• Comparison of evidence
• Conclusion
• References
2

Patient Care Scenario
• A.G. is a 48-year-old man with no significant medical history. He presents
with a stabbing sensation in his middle back and additional pain in his
chest. His social history includes cigarette smoking, 1 pack/day, for the
past 15 years. Chest radiography in the ED reveals mediastinal widening.
Cardiac enzymes are within normal limits. The patient’s laboratory test
results include Na 142 mEq/L, K 3.8 mEq/L, SCr 0.82 mg/dL, glucose 142
mg/dL, total bilirubin 0.7 mg/dL, and ALT 31 U/L. He is rushed for a chest
CT with angiography, which reveals an acute type B aortic dissection. His
vital signs include blood pressure 210/122 mmHg and heart rate 130 bpm.
• Determine the appropriate management for A.G., including classification,
goal(s), and treatment modalities.
3

Hypertensive Emergency
• It is a type of hypertensive crisis with an elevated blood pressure
>180/120mg and associated acute hypertension-mediated organ
dysfunction (aHMOD)
4

Classification of Blood Pressure for Adults
Category Systolic Blood Pressure (mmHg) Diastolic Blood Pressure (mmHg)
Normal <120 <80
Pre-hypertension 120-129 <80
Hypertension - Stage I 130-139 80-89
Hypertension - Stage II ≥140 ≥90
Hypertensive Emergency
(end organ dysfunction)
>180 >120
5

Epidemiology
• Hypertension is a serious medical condition that significantly increases
the risk of heart, brain, kidney and other disease as well as premature
death
• An estimated 1.28 billion adults 30-79 years worldwide have
hypertension, 2/3 living in LMICs
• 25% of hypertensive crisis that presents to the ED are hypertensive
emergencies
6

Risk Factors
• Non-adherence to antihypertensive medications (poorly controlled BP)
• Female sex (a 2014 systematic review by Pak et al.)
• Age
• Obesity
• Pre-existing DM or CAD
• Mental illness
• Sedentary lifestyle
• Etc.
7

Pathophysiology
• Auto-regulatory changes in vascular resistance through the autocrine/paracrine
system occur in response to the production of endogenous vasoconstrictors (e.g.
catecholamines, Ag II) or endogenous vasodilators (e.g., nitric oxide)
• During a hypertensive emergency, acute elevation in blood pressure overwhelms the
autoregulation of the endothelial control of vascular tone, leading to mechanical
vascular wall stress with subsequent endothelial damage and vascular permeability
• This permeability leads to the leakage of plasma into the vascular wall, resulting in
activation of platelets, initiation of the coagulation cascade, deposition of fibrin, and
recruitment of inflammatory mediators
• This inappropriate vasoconstriction and microvascular thrombosis leads to
hypoperfusion and end-organ ischemia with subsequent target-organ dysfunction
8

Signs & Symptoms
Symptoms Signs
Headache Seizures
Chest pain Neck rigidity
Shortness of breath Lung crepitation
Nausea Severely elevated BP (for age)
Vomiting
Confusion
Seizures
Unconsciousness
9

Initial Treatment
• No RCTs to assess clinical outcomes, comparing different rates of
decline in blood pressure among patients and choice of medication
• Rapid reduction of blood pressure might result in reduced cerebral
perfusion
• Short acting titratable intravenous antihypertensive are therefore
recommended
• JNC 7 recommends MAP reduction by <25% within the first 2 hours
and to around 160/100-110 mmHg over the next 6 hours
NB: In aortic dissection, systolic BP reduced <120 mmHg within 20
minutes with adequate cerebral, coronary, and renal perfusion
10

Initial Treatment
• Choice of the antihypertensive agent is often based on
• Target organ dysfunction
• Mechanism of drug action
• Availability
• Ease of administration
• Contraindication
• Side effects
• Institutional culture
• Physician preference
11

Treatment Goals
12
Dual oral therapy is recommended when the blood pressure exceeds
180/110 mmHg (STG, 2017)

Pharmacological Management
• Hydralazine
• Labetalol
• Sodium nitroprusside
• Nitroglycerin
• Fenoldopam
• Nicardipine
• Clevidipine
• Phentolamine
• Etc.
NB: No single drug has been proved to be more beneficial than the others in this
clinical setting. 13

Labetalol
• It is an arterial vasodilator through its α1 receptor antagonism
• Also a 3rd generation non-selective β receptor antagonist
• block presynaptic β1 receptors
• ↓ cardiac output, ↓ afterload
• Intrinsic sympathomimetic activity (ISA)
• Local anesthetic effect
• Low lipid solubility so is less likely to enter the brain, and may
therefore cause less sleep disturbance and nightmares
14

Hydralazine
• A direct arteriolar vasodilator with little effect on veins often used as
an antihypertensive
• It decreases systemic vascular resistance, which subsequently
decreases BP
• P’kinetic polymorphism: slow and rapid acetylators (HLA-DR4w) →
SLE
• It is not recommended for use in hypertensive crisis because of its
unpredictable antihypertensive effect and difficulty in titration
• It is often times used in pregnancy related hypertensive crisis because
it is not teratogenic and increases the uterine blood flow
15

PHARMACODYNAMICS
Parameter CAD Hydralazine Labetalol
Preload ↔ ↔
Afterload ↓ ↓
Cardiac output ↑ ↓
Contraindication Dissecting aortic aneurysm
ACS
Mitral valve rheumatic heart disease
CVA
CAD
Severe bradycardia
2nd & 3rd degree heart block
Bronchial asthma
Recent cocaine use
Pheochromocytoma
Acute decompensated heart failure
Side effects Headache, hypotension, palpitations,
tachycardia, peripheral edema, SLE, nausea
and vomiting etc.
Lightheadedness, dizziness, nausea,
fatigue etc.
16

PHARMACOKINETICS
Parameter Hydralazine Labetalol
Dose; IV bolus
infusion
5-10mg IV over 2 min 20mg over 2 min
1-2mg/min
Onset 10-20min 2-5min
Duration 1-4 hours 2-4 hours
Protein binding 85-90% 50%
Volume of distribution 0,3-8.2L/kg 3-16L/kg
Metabolism Acetylation in liver into inactive metabolites
(phthalazine, pyruvic acid hydrazine)
Conjugation to glucuronide
metabolites
Half life 2-8 hours (normal renal function)
7-16 hours (ESRD)
5.5 hours
Excretion Urine (14% unchanged) Urine (55-60%)
Feces via bile
17

Hydralazine or Labetalol?
Hydralazine Labetalol
PIH (Pre-eclampsia, Eclampsia): SBP between 140-160
mmHg and DBP between 90-105 mmHg (ACOG, 2002;
Magee et al., 2003)
Hypertensive encephalopathy (MAP: 20-25%, DBP:100-
110mmHg) (Vaughan and Delanty, 2000)
Ischemic stroke: BP>220/120mmHg (Adamms et al., 2003;
Bath, 2004)
Hemorrhagic stroke: BP<180/110mmHg (Adamms et al,
2003) MAP: <130mmHg AHA (Broderick et al., 1999)
SAH: SBP>15% (Kraus et al., 2002) SBP<20% (Sen et al.,
2003)
ACS: β-blocking effect decrease cardiac workload and
improve symptoms
Acute aortic dissection: SBP<120mmHg HR<60bpm
PIH: safe and efficacious (Magee et al., 2003) 18

Comparative data in hypertensive emergency
Agents compared Population Study design Key findings
Labetalol vs.
Hydralazine
(Delgado De
Pasquale et al., 2014)
Hypertensive crisis in pregnant
(24 wks’ gestation or more)
patients:
(74% severe preeclampsia,
~12% chronic HTN with
superimposed preeclampsia,
~12% chronic HTN, 1.5%
eclampsia)
Treat if SBP ≥ 160 mm Hg
and/or DBP ≥ 110 mm Hg
n=261
Prospective,
randomized
No difference in BP control efficacy
determined by achieving SBP, DBP,
and MAP goal
No difference in need for rescue
therapy or adverse effects
19

Labetalol vs.
Hydralazine
(Vigil-De Gracia et al.,
2006)
Severe hypertension
associated with pregnancy
(~55% severe preeclampsia,
~18% gestational HTN, 15%
chronic HTN with
superimposed preeclampsia,
1.5% with eclampsia)
Treat if SBP ≥ 160 mm Hg
and/or DBP ≥ 110 mm Hg
n=200
Prospective,
randomized
No difference in attainment of
BP goals
More maternal palpitations
(p=0.01), tachycardia (p<0.05)
with hydralazine than
with labetalol
More neonatal bradycardia
(p=0.008) and hypotension
(p<0.05) with labetalol than with
Hydralazine
20

Labetalol vs.
Hydralazine
(Khan et al., 2017)
Severe hypertension
associated with pregnancy
(~55% severe
preeclampsia, ~45%
gestational HTN)
Treat if SBP ≥ 160 mm
Hg and/or DBP ≥ 110 mm
Hg
n=78
Prospective,
randomized
Labetalol lowered MAP
more than hydralazine
(p=0.046)
21

Hydralazine for treatment of severe hypertension
in pregnancy: meta-analysis (Magee et al., 2003)
• Meta-analysis of 21 RCTs (893 women) published between 1966 and
September 2002, of short acting anti-hypertensives for severe
hypertension in pregnancy
• 8 RCTs compared hydralazine and nifedipine
• 5 RCTs compared hydralazine to labetalol
NB: There was significant heterogeneity in outcome between trials and
differences in methodological quality
22

Outcome
• Hydralazine was associated with
• a trend towards less persistent severe hypertension than labetalol (relative risk 0.29 (95%
confidence interval 0.08 to 1.04); two trials), but more severe hypertension than nifedipine (1.41
(0.95 to 2.09); four trials)
• more maternal hypotension (3.29 (1.50 to 7.23); 13 trials)
• more caesarean sections (1.30 (1.08 to 1.59); 14 trials)
• more placental abruption (4.17 (1.19 to 14.28); five trials)
• more maternal oliguria (4.00 (1.22 to 12.50); three trials)
• more adverse effects on fetal heart rate (2.04 (1.32 to 3.16); 12 trials)
• more low Apgar scores at one minute (2.70 (1.27 to 5.88); three trials)
• more maternal side effects (1.50 (1.16 to 1.94); 12 trials) and
• with less neonatal bradycardia than labetalol (risk difference –0.24 (–0.42 to –0.06); three trials).
NB: For all but Apgar scores, analysis by risk difference showed heterogeneity between trials.
23

Recommendation
• Outcome does not support the use of hydralazine as first line for the
treatment of PIH
• Adequately powered clinical trials are needed, with a comparison of
LABETALOL and nifedipine showing the most promise.
24

Comparative study of intravenous hydralazine and
labetalol in severe hypertensive disorders of
pregnancy (Kumari et al., 2020)
• A prospective study was conducted among 100 women admitted with SBP ≥
160 or DBP ≥ 110 mmHg or both
• More significant decrease in SBP, DBP and MAP at the end of 15 and 30
minutes in labetalol group.
• Labetalol required fewer doses as compared to hydralazine to achieve the
target BP (average 1.95 versus 3.1).
• Total numbers of term deliveries were 19 (38%) in hydralazine group and
16 (32%) in labetalol group.
• Pre-term deliveries in hydralazine and labetalol group were 14 (28%) and
17 (34%) respectively.
• Headache was significantly more common in hydralazine treated patients
than labetalol group.
25

Response of drugs on blood pressure
26

Dose required to achieve target blood pressure
27

Side effect of drugs
28

Mode of delivery
29

Fetal outcome
30

Comparison of Efficacy and Safety of Intravenous
Labetalol Versus Hydralazine for Management of
Severe Hypertension in Pregnancy (Patel et al., 2018)
• A prospective randomized controlled trial of 152 eligible subjects were
randomized in two groups consisting 76 subjects each
• Fetal outcome was comparable in both groups.
31

32

INTERLUDE
Luke 19:26
FOR I SAY UNTO YOU, THAT UNTO EVERY ONE WHICH
HATH SHALL BE GIVEN; AND FROM HIM THAT HATH NOT,
EVEN THAT HE HATH SHALL BE TAKEN AWAY FROM HIM
(KJV)
33

Hydralazine or Labetalol?
Hydralazine Labetalol
PIH (Pre-eclampsia, Eclampsia): SBP between 140-
160 mmHg and DBP between 90-105 mmHg (ACOG,
2002; Magee et al., 2003)
Hypertensive encephalopathy (MAP: 20-25%,
DBP:100-110mmHg) (Vaughan and Delanty, 2000)
Ischemic stroke: BP>220/120mmHg (Adamms et al.,
2003; Bath, 2004)
Hemorrhagic stroke: BP<180/110mmHg (Adamms et
al, 2003) MAP: <130mmHg AHA (Broderick et al.,
1999)
SAH: SBP>15% (Kraus et al., 2002) SBP<20% (Sen
et al., 2003)
ACS: β-blocking effect decrease cardiac workload and
improve symptoms
Acute aortic dissection
PIH: safe and efficacious (Magee et al., 2003)
34

Practice Points
• The first step in assessing a patient for hypertensive emergency is
determining the presence of target-organ damage.
• Target-organ damage assessment often stems from patient-specific chief
complaints, physical examination findings, routine and directed
laboratory test assessments, and use of diagnostic examinations.
• After patients are confirmed to have a hypertensive emergency, they
must be screened for exceptions (e.g., stroke, pregnancy-associated
acute hypertension, and aortic dissection) to the general principles of
treatment, which will allow for target goal development.
• In general hypertensive emergencies (i.e., without exceptions), the goal
in the first 60 minutes of treatment is to reduce the MAP by 25%
35

Practice Points
• Patients with exceptions have unique treatment goals leading to unique
medication selection.
• The goal of medication selection is to provide “smooth” BP reduction,
optimizing BPV with agents that are readily titrated while avoiding
complications because of adverse effects.
• Knowledge of the PK, PD, hemodynamics, and adverse effect profiles
of the available options is warranted.
36

Patient Case Scenario
• A.G. is a 48-year-old man with no significant medical history. He
presents with a stabbing sensation in his middle back and additional
pain in his chest. His social history includes cigarette smoking, 1
pack/day, for the past 15 years. Chest radiography in the ED reveals
mediastinal widening. Cardiac enzymes are within normal limits. The
patient’s laboratory test results include Na 142 mEq/L, K 3.8 mEq/L,
SCr 0.82 mg/dL, glucose 142 mg/dL, total bilirubin 0.7 mg/dL, and
ALT 31 U/L. He is rushed for a chest CT with angiography, which
reveals an acute type B aortic dissection. His vital signs include blood
pressure 210/122 mm Hg and heart rate 130 bpm.
• Determine the appropriate management for A.G., including
classification, goal(s), and treatment modalities.
37

CONCLUSION
• Labetalol is recommended for use in hypertensive encephalopathy,
CVA, ACS, acute aortic dissection, PIH
• Hydralazine is recommended ONLY in PIH??
38

CONCLUSION
• WHO suggests that pharmacological treatment of hypertension can be
provided by non-physician professionals such as PHARMACISTS
and nurses, as long as the following conditions are met: proper
training, prescribing authority, specific management protocols and
physician oversight
39

REFERENCES
• World Health Organization (2021). Hypertension
• Walls et al. (2017). Rosen’s emergency medicine; concepts and
clinical practice
• Pak et al. (2014). Acute hypertension: a systematic review and
appraisal of guidelines. The Ochsner Journal. 14(4):655-663
• World Health Organization (2021). Guideline for the pharmacological
treatment of hypertension in adults
• STG (2017), 7th Edition. Ministry of Health. Ghana National Drug
Policy. Page:154-155
40

REFERENCES
• Mallidi et al. (2013). Management of hypertensive emergencies. J
Hypertens:2 (2)
• Chobanian et al. (2003). Seventh Report of the Joint Committee on
prevention, detection, evaluation and treatment of high blood pressure.
Hypertension 42:1206-1252
• Mark, P.E., and Rivera, R. (2011). Hypertensive emergencies: an update.
Curr Opin Crit Care 17:569-580
• Kraus et al., (2002). Critical care issues in stroke and subarachnoid
hemorrhage. Neurol Res 24:47-47
• Sen et al. (2003). Tripple-H therapy in the management of aneurysmal
subarachnoid hemorrhage. Lancet Neurol 2:614-621
41

REFERENCES
• Magee et al. (2003). Hydralazine for treatment of severe hypertension
in pregnancy: meta-analysis. BMJ: 327:1-10
• Kumari et al. (2020). Comparative study of intravenous hydralazine
and labetalol in severe hypertensive disorders of pregnancy. Int J
Reprod Contracept Obstet Gynecol;9(2):675-681
• Patel et al. (2018). Comparison of Efficacy and Safety of Intravenous
Labetalol Versus Hydralazine for Management of Severe Hypertension
in Pregnancy. The Journal of Obstetrics and Gynecology of India. 68
(5):376–381
• Aronow, W.S. (2017). Treatment of hypertensive emergencies. Ann
Transl Med;5(Suppl 1):S5
42

REFERENCES
• STG (2017), 7th Edition. Ministry of Health. Ghana National Drug
Policy. Page: 147-156
• Delgado De Pasquale et al. (2014). Hydralazine vs. labetalol for the
treatment of severe hypertensive disorders of pregnancy. A
randomized, controlled trial. Pregnancy Hypertens ;4:19-22.
• Vigil-De Gracia et al.(2006). Severe hypertension in pregnancy:
hydralazine or labetalol: a randomized clinical trial. Eur J Obstet
Gynecol Reprod Biol;126:157-62
• Benken, S.T. (2018). Hypertensive Emergencies. Medical Issues in the
ICU. CCSAP
43

REFERENCES
• Khan et al. (2017). Comparison of Hydralazine and Labetalol to lower
severe hypertension in pregnancy. Pak J Med Sci.;33(2):466-470.
• Vaughan, C.J., and Delanty, N. (2000). Hypertensive emergencies. The
Lancet. Vol 356:411-417
• Clinical Practice Guidelines. Management of Hypertension. 5th
Edition (2018)
44

ACKNOWLEDGEMENT
Dr Amos Adapalala Bugri (DDP)
45

THANK YOU
46

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