Hypertensive emergency (crisis) – Drugs, doses & management

This drug manual is provided for use in patients with hypertensive emergency (also referred to as hypertensive crisis or malignant hypertension). Hypertensive emergency is defined as significantly elevated blood pressure (systolic pressure ≥180 mmHg and/or diastolic pressure ≥120 mmHg) with concurrent signs of acute organ damage or failure. Any of the drugs listed below may be used to treat hypertensive emergencies. The desired time to action, contraindications, and risk of adverse effects should guide the choice of agent.

Calcium channel blockers (CCB)

Clevidipine

Drug	Clevidipine
Brand names	Cleviprex ®
Indications	Hypertension and hypertensive emergency. Treatment of postoperative hypertension.
Mechanism of action	Ultra-short-acting calcium channel blocker (CCB). Half-life: 5 minutes. Rapidly inactivated by esterases.
Effects	• Clevidipine is a dihydropyridine L-type calcium channel blocker. Clevidipine is highly selective for vascular smooth muscle cells and has little or no effect on myocardial contractility or conduction. Clevidipine reduces mean arterial blood pressure (MAP) by decreasing systemic vascular resistance (SVR). Clevidipine does not reduce cardiac filling pressure (pre-load), since it has no effects on the venous capacitance vessels. Hence, Clevidipine reduces blood pressure without affecting cardiac filling pressures. • Clevidipine is more effective than nitroglycerin, nitroprusside, and nicardipine in hypertensive emergencies.
Time to onset of action	2-4 minutes
Duration of action	5-15 minutes
Delivery	IV (infusion).
Dose	Initial dose: 1-2 mg/h IV. Increase as necessary. Rapid titration is possible. Maximum dose: 21 mg/h IV. Common therapeutic dose: 4-6 mg/h. Clevidipine is administered in lipid emulsion (containing soy, egg), of which the maximum dose per 24 hours is 1000 mL.
Adverse effects	Headache. Nausea. Fever. Atrial fibrillation. Worsening of heart failure.
Caution	• Used cautiously in patients with acute heart failure. • Clevidipine can cause reflex tachycardia. • Contraindicated in severe aortic stenosis due to risk of hypotension.

Nicardipine

Drug	Nicardipine
Brand names	Cardene ®
Indications	Hypertension, hypertensive emergency/crisis. Pregnancy-induced hypertension. Angina pectoris Prinzmetal’s angina
Mechanism of action	Nicardipine is a dihydropyridine calcium-channel blocker (CCB). Nicardipine inhibits the influx of extracellular calcium in the myocardial and peripheral vascular smooth muscle cell membranes, thus inhibiting the contraction of smooth muscle cells. As compared with nitroprusside, nicardipine induces relatively greater venodilation than arteriolar dilation.
Effects	Nicardipine causes dilation of the coronary and systemic arteries, decreases total peripheral resistance, decreases systemic blood pressure, and decreases afterload. Nicardipine has antianginal and antihypertensive effects.
Time to onset of action	5 to 15 minutes
Duration of action	1.5 to 5 hours
Delivery	IV
Dose	5–15 mg/hour IV infusion. Higher doses (up to 30 mg/hour) may be required in some patients.
Adverse effects	Tachycardia. Headache. Flushing. Edema. Dizziness.
Caution	Should be used cautiously in patients with myocardial ischemia and/or heart failure.

ACE inhibitors

Enalaprilat

Enalaprilat is rarely used in hypertensive crisis due to its slow onset, prolonged duration of effect, and significant individual variations in its effect.

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Drug	Enalaprilat
Brand names	Vasotec IV ®
Indications	Hypertension and hypertensive emergency. Acute left ventricular failure.
Mechanism of action	Enalaprilat is the active metabolite (ester) of enalapril, an angiotensin-converting enzyme (ACE) inhibitor. Enalaprilat lowers blood pressure by inhibiting ACE.
Effects	• The hypotensive effect of enalaprilat depends on plasma volume and plasma renin activity. Volume depletion and high plasma renin activity increase the effect of enalaprilat and may cause severe hypotension.
Time to onset of action	15 to 30 minutes.
Peak effect	Within hours.
Duration of effect	8 to 24 hours
Delivery	IV
Dose	Initial dose: 1.25 mg IV. Increase as necessary. Maximum dose: 5 mg IV every six hours.
Adverse effects	Severe hypotension.
Contraindications	• Contraindicated in pregnancy, severe renal artery stenosis, severe hyperkalemia. • Avoid in acute heart failure and acute myocardial infarction.

Beta-blockers

Esmolol

Drug	Esmolol
Brand names	Brevibloc ®
Indications	Short-term control of ventricular rate (including perioperative tachycardia) and hypertension (including hypertensive emergency, perioperative hypertension).
Mechanism of action	• Relatively cardioselective (beta-1 receptor blocker) beta-blocker with ultra-short acting effect. • Half-life: 9 minutes.
Effects	• Esmolol is a beta-adrenergic receptor blocker. • Esmolol lowers blood pressure immediately (within 1 minute). • Esmolol may also be used to control supraventricular tachycardia (rate control). • Esmolol may be used to reduce myocardial ischemia in the CCU or ICU.
Time to onset of action	1 minute
Duration of action	20-30 minutes
Delivery	IV
Dose	Loading dose: 500 μg/kg bolus over 1 minute. Infusion start dose: 25–50 μg/kg/min. Maximum infusion dose: 300 μg/kg/min. Bolus doses of 300 μg/kg can be repeated during infusion.
Adverse effects	Flushing. Nausea. Bronchospasm. AV block.
Caution	• Avoid in acute heart failure. • May cause bradycardia.

Labetalol

Drug	Labetalol
Brand names	Trandate ®
Indications	Myocardial ischemia. Hypertension. Hypertensive emergency, including in pregnancy. Postoperative hypertension.
Mechanism of action	Combined beta-adrenergic and alpha-adrenergic blocker with rapid onset of action. Labetalol has less antihypertensive efficacy compared with nicardipine. Labetalol is safe in patients with coronary artery disease since it does not increase heart rate and reduces myocardial oxygen consumption. Time to onset of action: 5 minutes.
Effects	Lowers blood pressure, reduces heart rate, myocardial oxygen consumption, and myocardial contractility.
Time to onset of action	5 to 10 minutes
Duration of action	2 to 4 hours
Delivery	IV
Dose	Can be given as repeated intravenous bolus injections or as a constant-dose infusion. Bolus regimen: • 20 mg IV bolus over 2 minutes, followed by 20 to 80 mg every 10 minutes to a total dose of 300 mg. Infusion regimen: • 0.5–2 mg/minute IV infusion. Higher doses are sometimes required.
Adverse effects	Vomiting. Dizziness. Nausea. Atrioventricular blocks (AV blocks). Orthostatic hypotension. Paresthesias (scalp tingling). Bronchospasm.
Caution	• Avoided in hypertensive emergencies with left ventricular failure (due to negative inotropic effect). • Used cautiously in patients with asthma (due to risk of bronchospasm). • Used cautiously in bradycardia due to negative chronotropic effect. • In patients with pheochromocytoma, cocaine, or methamphetamine overdose, prior treatment with alpha blockade is necessary before administering labetalol (risk of elevating blood pressure in these settings).

Metoprolol

Drug	Metoprolol
Brand names	Dutoprol ®, Kapspargo ®, Lopressor ®, Lopressor HCT ®, Toprol ®, Seloken ®
Indications	Myocardial ischemia. Hypertension périopératoire.
Mechanism of action	Bêta-1 bloquant adrénergique.
Effects	Réduit la pression artérielle, diminue la fréquence cardiaque, la consommation d’oxygène myocardique et la contractilité myocardique. Effet hypotenseur moins prononcé que l’esmolol et le labétalol.
Time to onset of action	20 minutes
Duration of action	5 à 8 heures
Delivery	IV
Dose	1,25 à 5 mg IV suivi de 2,5 à 15 mg IV toutes les 3 à 6 heures.
Adverse effects	Vomissements. Vertiges. Nausées. Blocs auriculo-ventriculaires (blocs AV). Hypotension orthostatique. Paresthésies (picotements du cuir chevelu). Bronchospasme.
Caution	• À éviter dans les urgences hypertensives avec insuffisance cardiaque aiguë. • Utilisé avec prudence chez les patients asthmatiques (en raison du risque de bronchospasme). • Utilisé avec prudence en cas de bradycardie en raison de l’effet chronotrope négatif.

Agonistes des récepteurs dopaminergiques

Fenoldopam

Drug	Fenoldopam
Brand names	Corlopam ®
Indications	Gestion à court terme de l’hypertension, y compris l’urgence hypertensive.
Mechanism of action	• Agoniste systémique des récepteurs Dopamine-1 (D1). • Réduit la pression artérielle tout en maintenant ou en augmentant la perfusion rénale.
Effects	Les agonistes des récepteurs Dopamine-1 abaissent la pression artérielle systémique et augmentent la perfusion rénale.
Time to onset of action	5 à 10 minutes
Duration of action	30 à 60 minutes
Delivery	IV
Dose	Dose initiale de perfusion : 0,1 μg/kg/minute IV. Ajustée à intervalles de 15 minutes. Dose maximale de perfusion : 1,6 μg/kg/minute
Adverse effects	Maux de tête. Bouffées de chaleur. Tachycardie. Nausées. Hypokaliémie. Augmentation de la pression intraoculaire chez les patients atteints de glaucome.
Caution	Utilisé avec prudence chez les patients atteints de glaucome ou ayant une pression intracrânienne élevée.

Agonistes alpha

Clonidine

Drug	Clonidine
Brand names	Catapresan ®, Catapres ®, Dixarit ®, Catapres-TTS ®, Catapres-TTS-1 ®, Duraclon ®, Kapvay ®
Indications	• Agitated delirium • Analgesia • Hypertension, hypertensive crisis/emergency
Mechanism of action	Clonidine is primarily a centrally acting alpha-2 agonist. Stimulation of alpha-2 adrenoceptors in the ventromedial and rostral-ventrolateral areas of the medulla results in the blood pressure-lowering effect.
Effects	Potent blood pressure-lowering effect. Pain relief.
Delivery	IV, IM, PO, transdermal
Dose	Injection IV: • 150 μg in 1 ml vial. Dilute with 10 ml of normal saline and give by slow injection over 5-10 minutes. Dilute immediately before use. PO: Alternatives: Dixarit 25 μg tablets. Catapres 150 μg tablets. Dose: 75 μg daily increased as required to up to 900 μg/day. Transdermal (one patch lasts for a week): • Catapres TTS-1 (0.1 mg/24 hrs). • Catapres TTS-2 (0.2 mg/24 hrs) • Catapres TTS-3 (0.3 mg/24 hrs) Dosage in renal failure and renal replacement therapy: Dose as in normal renal function
Adverse effects	Excessive sedation. Confusion. Hallucinations. Hypotension. Bradycardia. AV-block. Constipation.
Contraindications	Bradycardia.
Caution	• Clonidine may induce severe hypotension. • Clonidine is not recommended in most patients with severe cardiovascular disease or in those who are otherwise hemodynamically unstable. The benefit of its administration in these patients should be carefully balanced against the potential risks resulting from hypotension. • Withdrawal of clonidine may lead to rebound hypertension. Withdraw slowly. • Simultaneous use of tricyclic antidepressants reduces the effect of clonidine. • Clonidine increases the CNS-depressive effects of alcohol and sedatives.

Nitric oxide (NO) inducing drugs

Nitroglycerin

Patients using nitroglycerin regularly may have developed tolerance and require higher doses, or alternatively nitroprusside, to achieve the desirable blood pressure-lowering effect.

Drug	Nitroglycerin
Brand names	Gonitro ®, Minitran ®, Mylan-nitro ®, Nitro-bid ®, Nitro-dur ®, Nitroject ®, Nitrolingual ®, Nitromist ®, Nitrostat ®, Rectiv ®, Trinipatch ®
Indications	Œdème pulmonaire, insuffisance cardiaque congestive. Angine de poitrine. Hypertension, crise hypertensive/urgence hypertensive. Hypertension pulmonaire. Contrôle de la pression artérielle.
Mechanism of action	La nitroglycérine fournit de l’oxyde nitrique (NO) qui induit une vasodilatation (des artérioles et des veines) via la génération de GMP cyclique, qui active ensuite les canaux potassiques sensibles au calcium dans la membrane cellulaire. La nitroglycérine est similaire dans son action et sa pharmacocinétique au nitroprussiate, bien que ce dernier soit plus puissant.
Effects	Antihypertenseur. Antiangineux.
Time to onset of action	2 à 5 minutes
Duration of action	5 à 10 minutes
Delivery	IV
Dose	Dose initiale de perfusion : 5 μg/min. Augmenter de 5-10 μg/min toutes les 5 min jusqu’à la pression artérielle souhaitée. Dose maximale : 100 μg/min. Délai d’action : 2 à 5 minutes Durée d’action : 5 à 10 minutes.
Adverse effects	Céphalée (vasodilatation cérébrale). Tachycardie (due à l’activation sympathique réflexe). Nausées. Vomissements. Bouffées de chaleur. Palpitations. Tolérance avec utilisation prolongée. Méthémoglobinémie. Hypoxémie.
Caution	Procéder avec prudence dans les conditions dépendantes de la postcharge.

Nitroprussiate

Drug	Nitroprusside
Brand names	Nipride ®, Nipride RTU ®, Nitropress ®.
Indications	Œdème pulmonaire, insuffisance cardiaque congestive. Angine de poitrine. Hypertension, crise hypertensive/urgence hypertensive. Hypertension pulmonaire. Contrôle de la pression artérielle.
Mechanism of action	Le nitroprussiate fournit de l’oxyde nitrique (NO) qui induit une vasodilatation des artérioles et des veines via la génération de GMP cyclique, qui active ensuite les canaux potassiques sensibles au calcium dans la membrane cellulaire. Délai d’action : 1 minute. Durée d’action : <10 minutes.
Effects	Abaissement puissant de la pression artérielle. Effet antiangineux. Réduit la postcharge et la précharge. Efficace dans l’œdème pulmonaire. Peut provoquer une hypotension sévère.
Time to onset of action	30 secondes à 1 minute
Duration of action	1 à 10 minutes
Delivery	IV
Dose	Perfusion : Dose initiale : 0,25 à 0,5 μg/kg/minute. Augmentée si nécessaire (par paliers de 0,5 μg/kg/min). Dose maximale : 8-10 μg/kg/minute. Dose maximale courante : 3 μg/kg/minute. La dose maximale (10 μg/kg/minute) ne doit jamais être utilisée pendant plus de 10 minutes. Administrer du thiosulfate de sodium (cyanure en thiocyanate) et arrêter la perfusion de nitroprussiate si une toxicité au cyanure est suspectée.
Adverse effects	• Nausées. Vomissements. Agitation. Spasmes musculaires. Transpiration. Bouffées de chaleur. • Une utilisation prolongée à haute dose peut provoquer une toxicité au thiocyanate et au cyanure. Le nitroprussiate est métabolisé en cyanure. La toxicité au cyanure peut être fatale (doit être suspectée si le patient développe un état mental altéré et une acidose lactique). Les issues fatales sont rares. L’insuffisance rénale augmente le risque de toxicité au cyanure. La toxicité au cyanure nécessite des doses >2 μg/kg/minute. Utiliser la dose la plus faible possible, éviter une utilisation prolongée (<2-3 jours), et surveiller le patient de près pour éviter la toxicité au cyanure. • Réduction dose-dépendante de la perfusion coronaire et rénale. • Élévation dose-dépendante de la pression intracrânienne (PIC) et réduction du flux sanguin cérébral.
Caution	• Utilisé avec prudence chez les patients présentant une pression intracrânienne élevée ou une azotémie. • Ne doit pas être administré aux femmes enceintes. • Ne doit pas être administré aux patients atteints d’atrophie optique de Leber.

Autres médicaments

Phentolamine

Drug	Phentolamine
Brand names	Oraverse ®, Rogitine ®
Indications	Hypertensive crisis.
Mechanism of action	Phentolamine is a non-selective alpha-adrenergic blocker. Phentolamine reduces blood pressure while increasing catecholamine activity.
Effects	Primarily causes afterload reduction.
Time to onset of action	1 to 2 minutes
Duration of action	10 to 30 minutes
Delivery	IV
Dose	Bolus injection: 5 to 15 mg every 5 to 15 minutes as necessary. Continuous infusion: Start infusion at 0.1 mg/min and increase in increments of 0.1 mg.
Adverse effects	Tachycardia. Flushing. Headache. Nausea. Vomiting.
Caution	Rarely used unless the patient has a confirmed diagnosis of pheochromocytoma Treatment of hypertension associated with pheochromocytoma; treatment of dermal necrosis after extravasation of drugs with α-adrenergic effects.

Hydralazine

Not preferred for hypertensive emergencies due to the high risk of reflex sympathetic stimulation.

Drug	Hydralazine
Brand names	Apresoline ®, Bidil ®
Mechanism of action	• Induces arteriolar vasodilation. No effect on venous circulation. • May cause reflex sympathetic stimulation (can be counteracted with simultaneous administration of beta-blockers).
Effects	Induces arteriolar vasodilation without effects on venous circulation. The reduction in systemic vascular resistance (SVR) is rapid and may cause reflex sympathetic stimulation, including tachycardia. May therefore induce or worsen angina pectoris. The rapid reduction of afterload is desired in conditions requiring afterload reduction.
Time to onset of action	10-30 minutes.
Duration of action	<4 hours.
Delivery	IV or IM.
Dose	Injections • IV: 10–40 mg every 4–6 hours • IM: 10–20 mg every 4–6 hours. Infusion • Afterload reduction: Start infusion at 1 mg/hour. Increase by 0.5 mg/hour every 20 min to desired blood pressure. Maximum infusion rate 5 mg/hour. • Antihypertensive treatment: Start infusion at 5 mg/hour. Increase by 2.5 mg/hour every 20 min to desired blood pressure. Maximum infusion rate 25 mg/hour.
Adverse effects	Tachycardia. Flushing. Headache. Angina pectoris.
Caution	Heart failure. Angina pectoris (ischemic heart disease).

References

1. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Hypertension 2018; 71:e140-e144]. Hypertension 2018; 71:e13-e115.
2. Marik PE, Varon J. Hypertensive crises: Challenges and management. Chest 2007; 131:1949.
3. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42:1206.
4. Varon J. Treatment of acute severe hypertension: Current and newer agents. Drugs 2008; 68:283.