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.

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	Mycoardial 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 as 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 regime: • 20 mg IV bolus over 2 minutes, followed by 20 to 80 mg every 10 minutes to a total dose of 300 mg. Infusion regime: • 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	Mycoardial ischemia. Perioperative hypertension.
Mechanism of action	Beta-1 adrenergic blocker.
Effects	Lowers blood pressure, reduces heart rate, myocardial oxygen consumption and myocardial contractility. Less pronounced blood pressure lowering effect than esmolol and labetalol.
Time to onset of action	20 minutes
Duration of action	5 to 8 hours
Delivery	IV
Dose	1.25 to 5 mg IV followed by 2.5–15 mg IV every 3 to 6 hours.
Adverse effects	Vomiting. Dizziness. Nausea. Atrioventricular blocks (AV-blocks). Orthostatic hypotension. Paresthesias (scalp tingling). Bronchospasm.
Caution	• Avoided in hypertensive emergencies with acute heart failure. • Used cautiously in patients with asthma (due to risk of bronchospasm). • Used cautiously in bradycardia due to negative chronotropic effect.

Dopamin receptor agonists

Fenoldopam

Drug	Fenoldopam
Brand names	Corlopam ®
Indications	Short term management of hypertension, including hypertensive emergency.
Mechanism of action	• Systemic Dopamine-1 (D1) receptor agonist. • Lowers blood pressure while maintaining or increasing kidney perfusion.
Effects	Dopamine-1 receptor agonists lower systemic blood pressure and increase renal perfusion.
Time to onset of action	50 to 10 minutes
Duration of action	30 to 60 minutes
Delivery	IV
Dose	Initial infusion dose: 0.1 μg/kg/minute iv. Titrated at 15 minutes intervals. Maximum infusion dose: 1.6 μg/kg/minute
Adverse effects	Headache. Flushing. Tachycardia. Nausea. Hypokalemia. Increased intra-ocular pressure in patients with glaucoma.
Caution	Used cautiously in patients with glaucoma or increased intracranial pressure.

Alpha-agonists

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 result 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. Catapress 150 μg tablets. Dose: 75 μg daily increased as required to up to 900 μg/day. Transdermal (one patch lasts for a week): • Catapress TTS-1 (0.1 mg/24hrs). • Catapress TTS-2 (0.2 mg/24hrs) • Catapress TTS-3 (0.3 mg/24hrs) 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
Contra indications	Bradycardia.
Caution	• Clonidine may induce severe hypotension. • Clonidine is not recommended in most patients with severe cardiovascular disease or in those who are otherwise haemodynamically 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, alternatively nitroprusside to achieve desirable blood pressure lowring effect.

Drug	Nitroglycerin
Brand names	Gonitro ®, Minitran ®, Mylan-nitro ®, Nitro-bid ®, Nitro-dur ®, Nitroject ®, Nitrolingual ®, Nitromist ®, Nitrostat ®, Rectiv ®, Trinipatch ®
Indications	Pulmonary edema, congestive heart failure. Angina pectoris. Hypertension, hypertensive crisis/emergency. Pulmonary hypertension. Blood pressure control.
Mechanism of action	Nitroglycerin provides nitric oxide (NO) that induces vasodilatation (of both arterioles and veins) via generation of cyclic GMP, which then activates calcium-sensitive potassium channels in the cell membrane. Nitroglycerin is similar in action and pharmacokinetics to nitroprusside, although the latter is more potent.
Effects	Antihypertensive. Antianginal.
Time to onset of action	2 to 5 minutes
Duration of action	5 to 10 minutes
Delivery	IV
Dose	Initial infusion dose: 5 μg/min. Increase by 5-10 μg/min every 5 min to desired blood pressure. Maximum dose: 100 μg/min. Time to onset of action: 2 to 5 minutes Duration of action: 5 to 10 minutes.
Adverse effects	Headache (cerebral vasodilation). Tachycardia (due to reflex sympathetic activation). Nausea. Vomiting. Flushing. Palpitations. Tolerance with prolonged use. Methemoglobinemia. Hypoxemia.
Caution	Proceed with caution in afterload-dependent conditions.

Nitroprusside

Drug	Nitroprusside
Brand names	Nipride ®, Nipride RTU ®, Nitropress ®.
Indications	Pulmonary edema, congestive heart failure. Angina pectoris. Hypertension, hypertensive crisis/emergency. Pulmonary hypertension. Blood pressure control.
Mechanism of action	Nitroprusside provides nitric oxide (NO) that induces vasodilatation of both arterioles and veins via generation of cyclic GMP, which then activates calcium-sensitive potassium channels in the cell membrane. Time to onset of action: 1 minute. Duration of action: <10 minutes.
Effects	Potent blood pressure lowering. Antianginal effect. Reduces afterload and preload. Effective in pulmonary edema. Can produce severe hypotension.
Time to onset of action	30 seconds to 1 minute
Duration of action	1 to 10 minutes
Delivery	IV
Dose	Infusion: Starting dose: 0.25 to 0.5 μg/kg/minute. Increased as necessary (increments of 0.5 μg/kg/min). Maximum dose: 8-10 μg/kg/minute. Common maximum dose: 3 μg/kg/minute. Maximum dose (10 μg/kg/minute) should never be used for mor than 10 minutes. Administer sodium thiosulfate (cyanide into thiocyanate) and terminate infusion of nitroprusside if cyanide toxicity is suspected.
Adverse effects	• Nausea. Vomiting. Agitation. Muscle spasm. Sweating. Flushing. • Prolonged high-dose use may cause thiocyanate and cyanide toxicity. Nitroprusside is metabolized to cyanide. Cyanid toxicity may be fatal (should be suspected if patient develops altered mental status and lactic acidosis). Fatal outcomes are rare. Renal failure increases risk of cyanide toxicity. Cyanide toxicity requires doses >2 μg/kg/minute. Use the lowest possible dose, avoiding prolonged use (<2-3 days), and monitor the patient closely to avoid cyanide toxicity. • Dose-dependent reduction in coronary and renal perfusion. • Dose-dependent elevation of intracranial pressure (ICP) and reduction in cerebral blood flow.
Caution	• Used cautiously in patients with high intracranial pressure or azotemia. • Should not be given to pregnant women. • Should not be given to patients with Leber optic atrophy.

Other drugs

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 patient has a confirmed diagnosis of pheochromocytoma Treatment of hypertension associated with pheochromocytoma; treatment of dermal necrosis after extravasation of drugs with á-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.